3,4-dihydro-1H-isoquinolin-2-yl-derivatives

ABSTRACT

The present invention relates to novel compounds of formula I wherein the variable groups are as defined in the claims or a pharmaceutically acceptable acid addition salt thereof. The compounds of the invention are NK2 antagonists.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is the 371 national stage application ofinternational application no. PCT/DK02/00858, filed Dec. 16, 2002, andclaims the benefit of priority under 35 U.S.C. §119(e) of U.S.provisional application 60/341,905, filed Dec. 19, 2001, and the benefitof priority under 35 U.S.C. §119(a)-(d) of Danish applicationPA200101916, filed Dec. 19, 2001. All of the aforementioned applicationsare hereby incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The compounds of the present invention belong to a novel class of3,4-dihydro-1H-isoquinolin-2-yl-derivatives having affinity for theneurokinin 2 (NK2) receptor. The compounds are NK2-antagonists and areuseful in the treatment of those diseases where an NK2-receptor isimplicated like asthma and a CNS-disease. These novel3,4-dihydro-1H-isoquinolin-2-yl-derivatives are capable of penetratingthe blood brain barrier and therefore useful in treating a variety ofCNS diseases.

BACKGROUND OF THE INVENTION

Three tachykinins, Substance P (SP), neurokinin A (NKA) and neurokinin B(NKB) are widely distributed throughout the peripheral and centralnervous systems. The biological effects of these neuropeptides arecarried out via binding to their preferred receptors, NK1, NK2 and NK3(Guard, S. and Watson, S. P. Neurochem. Int. 1991, 18, 149). Substance Pdisplays highest affinity for the NK1 receptors, whereas NKA and NKBbind preferentially to NK2 and NK3 receptors, respectively. Theselectivities of the endogenous ligands for their respective receptorsare not absolute (reviewed in Regoli, D. et al. Pharmacol. Rev. 1994,46, No. 4, 551 plus Bremer, A. A. et al. Eur J Pharmacol 2001, 423,143). The three receptor subtypes belong to the G-protein-coupledreceptor super family and have been cloned in various species includingmice, rats and humans (Giardina, G. A. M. et al. Drugs of the Future1997, 22, 1235 and references herein).

Activation of the tachykinin receptors influences a broad array ofbiological actions, including pain transmission, vasodilation, smoothmuscle contraction, secretion of saliva, bronchoconstriction, activationof the immune system (inflammatory pain), neurogenic inflammation andneurotransmission (Patacchini, R. et Maggi, C. A. Eur J Pharmacol. 2001,429, 13; Longmore, J. et al. Can J Physiol Pharmacol 1997, 75, 612;Giardina, G. A. M. et al. Drugs of the Future 1997, 22, 1235 andreferences herein).

Expression of NK2 receptors in human is somewhat controversial. Thereceptor is generally expressed in low amounts in CNS, andautoradiographic studies have failed to show NK2 receptors in the humanbrain. A recent reverse transcription-polymerase chain reaction (RT-PCR)study, however, has revealed a detectable expression of NK2 receptormRNA in various human brain regions including caudate nucleus, putamen,hippocampus, substantia nigra and cerebral cortex (Bensaid, M et al.Neurosci Lett 2001, 303, 25).

Up-regulation of the preprotachykinin (PPT) genes and mRNAs for theneurokinin receptors occurs both in animal models of disease (Fischer,A. et al. J Clin Invest 1996, 98, 2284) and in human diseases, such asasthma (Adcock, I. M. et al. J Mol Endocrino 1993, 11, 1).

NK antagonists have been and are under investigations for the treatmentof a vast amount of both CNS related and peripheral diseases. A numberof pre-clinical studies have been performed to assess the involvement ofNK1 and NK2 receptors mediation and modulation of diseases related toanxiety and/or depression (Griebel, G. Et al. Psychopharmacology, 2001,158, 241; Walsh, D. M. et al. Psychopharmacology 1995, 121, 186;Rupniak, N. M. et al. Neuropharmacology 2000, 39, 1413; Rupniak, N. M.et Kramer, M. S. TiPS 1999, 20, 485; ; Giardina, G. A. M. et al. Drugsof the Future 1997, 22, 1235, and references in these).

These studies indicate that NK2 antagonists will be useful in treatingor preventing a variety of brain disorders including depression, manicdepression, bipolar disorder, dysthymia, mixed anxiety depression,generalised anxiety disorder, social anxiety disorder, panic anxietydisorder, post traumatic stress disorder, obsessive compulsive disorder,acute stress disorder, phobia, pre-menstrual dysphoric disorder,psychosis, and Huntington's disease as well as Parkinson's disease,adjustment disorders, pain, emesis, migraine, epilepsia, obesity, asthmaand cerebrovascular disease. However, peripheral diseases such asinflammation, inflammatory bowel disease, hypertension, arthritis,cardiovascular diseases, neuritis, neuralgia, urticaria, incontinence,gastrointestinal diseases, influenza, allergy, pulmonary allergy andcarcinoma/tumoral growth may also be addressed by NK2 antagonists.

U.S. Pat. No. 3,994,891 discloses tetrahydroisoquinolines of the generalformula

wherein R is hydrogen or methyl, and G is NH or CH₂. The dihydroxycompounds are described as effective vasodilators, whereas the dimethoxycompounds are intermediates in the manufacture of the dihydroxycompounds.

Hence, there is a desire for novel compounds that are antagonists at theNK2 receptor.

SUMMARY OF THE INVENTION

The objective of the present invention is to provide compounds that areantagonists at the NK2 receptor.

A further objective of the present invention is to provide compoundswith such activities which have improved solubility, metabolic stabilityand/or bioavailability compared to prior art compounds.

Accordingly, the present invention relates to novel compounds of formulaI

wherein

-   R¹ is a group R¹¹CO—, R¹¹CS—, R¹¹SO₂—, R¹¹OCO—, R¹¹SCO— or    R¹¹CO—CR¹²R¹³— wherein R¹¹ is C₁₋₁₂-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl,    aryl-C₁₋₆-alkyl, heteroaryl, heteroaryl-C₁₋₆-alkyl,    tetrahydropyranyl, 1,2,3,4-tetrahydronaphtalenyl, or    4H-benzo[1,3]dioxinyl optionally substituted with halogen wherein    each of said C₁₋₆-alkyl, aryl, heteroaryl and C₃₋₈-cycloalkyl groups    independently are unsubstituted or substituted with one or more    substituents selected from the group comprising halogen, C₁₋₆-alkyl,    C₁₋₆-alkoxy, aryl-C₁₋₆-alkoxy, C₁₋₆-alkylsulfanyl, aryl and aryloxy    wherein said aryl and aryloxy independently are unsubstituted or    substituted with one or more halogen, and R¹² and R¹³ independently    are hydrogen or C₁₋₆-alkyl; or R¹ is a group R¹⁴R¹⁵NCO—, R¹⁴R¹⁵NCS—,    wherein R¹⁴ and R¹⁵ are independently hydrogen, C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl or aryl-C₁₋₆-alkyl, wherein each of    said C₁₋₆-alkyl, aryl and C₃₋₈-cycloalkyl groups independently are    unsubstituted or substituted with one or more substituents selected    from the group comprising halogen, C₁₋₆-alkyl and C₁₋₆-alkoxy, or    R¹⁴ and R¹⁵ together with the N-atom to which they are linked, form    a pyrrolidinyl, piperidinyl or perhydroazepinyl group;-   R² is selected from hydrogen, trifluoromethyl and C₁₋₆-alkyl;-   R³-R⁶, R^(7a), R^(7b), R^(8a) and R^(8b) are independently selected    from hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino,    C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl,    aminocarbonyl, C₁₋₆-alkylaminocarbonyl,    di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₄-alkoxy, C₁₋₆-alkylthio, hydroxy,    trifluoromethyl, trifluoromethylsulfonyl and C₁₋₆-alkylsulfonyl;-   m is 2-6;-   R⁹ is benzyl, benzoyl, 2,3-dihydrobenzofuranyl or mono- or bicyclic    aryl or heteroaryl wherein each benzyl, benzoyl, aryl or heteroaryl    optionally is substituted with one or more substituents selected    from halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,    di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,    C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,    C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl,    fluoromethyl and trifluoromethylsulfonyl;-   Q is C, N or CR¹⁰;-   wherein R¹⁰ is selected from hydrogen, halogen, cyano, nitro,    C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,    di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,    C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,    C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl,    fluoromethyl, trifluoromethylsulfonyl, a group —NR³⁰COR³¹ wherein    R³⁰ is hydrogen or C₁₋₆-alkyl and R³¹ is C₁₋₆-alkyl, a group —COOR¹⁶    wherein R¹⁶ is hydrogen or C₁₋₆-alkyl, or a group —CONR¹⁷R¹⁵ wherein    R¹⁷ and R¹⁸ independently are selected from hydrogen and C₁₋₆-alkyl    or R¹⁷ and R¹⁸ together with the nitrogen to which they are attached    form a piperidinyl, piperazinyl or morpholinyl, wherein said    piperidinyl, piperazinyl and morpholinyl is unsubstituted or    substituted with a C₁₋₆-alkyl;    or R⁹ and R¹⁰ together with the carbon to which they are attached    form a cyclic structure selected from the group comprising:

wherein Q′ is the carbon shared with the piperidine ring, so that saidcyclic structure together with said piperidine ring form a spirostructure; and

-   X, Y, and Z are independently chosen from O; NR¹⁹; CR²³R²⁴; S(O)_(n)    and a bond; wherein R¹⁹ is selected from hydrogen, C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkyl-C₁₋₆-alkyl, trifluoromethyl, acyl, thioacyl and    trifluoromethylsulfonyl, or R¹⁹ is a group R²⁰SO₂—, R²⁰OCO— or    R²⁰SCO— wherein R²⁰ is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl or aryl, or R¹⁹ is a    group R²¹R²²NCO— or R²¹R²²NCS—, wherein R²¹ and R²² are    independently hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, or aryl, wherein said    aryl is unsubstituted or substituted with one or more substituents    selected from C₁₋₆-alkyl or halogen; or R²¹ and R²² together with    the N-atom to which they are linked, form a pyrrolidinyl,    piperidinyl or perhydroazepinyl group; R²³ and R²⁴ are independently    selected from hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, heteroaryl, wherein said aryl is    unsubstituted or substituted with one or more substituents selected    from C₁₋₆-alkyl or halogen, amino, C₁₋₆-alkylamino, a group NR²⁵R²⁶    wherein R²⁵ and R²⁶ are independently selected from C₁₋₆-alkyl    C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl,    di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,    trifluoromethyl, trifluoromethylsulfonyl and C₁₋₆-alkylsulfonyl or    R²⁵ and R²⁶ together with the N-atom to which they are linked, form    a pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group,    or R²³ and R²⁴ together is oxo; and n is 0, 1 or 2; provided that no    more than one of X, Y and Z may be a bond, and provided that two    adjacent groups X, Y or Z may not at the same time be selected from    O and S; and-   A¹, A², A³ and A⁴ are independently selected from N and CR²⁷ wherein    R²⁷ is hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,    C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl,    di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,    trifluoromethyl, difluoromethyl, fluoromethyl,    trifluoromethylsulfonyl C₁₋₆-alkylsulfonyl amino or a group NR²⁸R²⁹    wherein R²⁸ and R²⁹ are independently selected from hydrogen and    C₁₋₆-alkyl or R²⁸ and R²⁹ together with the N-atom to which they are    linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl or    morpholinyl group; provided that only one of A¹, A², A³ and A⁴ may    be N; and    the dotted line emanating from Q is a bond when Q is C, and no bond    when Q is CR¹⁰ or N;    or a pharmaceutically acceptable acid addition salt thereof

DETAILED DESCRIPTION OF THE INVENTION

The C₁₋₁₂-alkyl groups defined for R¹¹ are preferably selected fromC₁₋₁₀-alkyl, more preferred C₁₋₈-alkyl, and most preferred C₃₋₈-alkyl.

In one embodiment, the present invention relates to such compoundswherein Q is CR¹⁰, and R⁹ and R¹⁰ together with the carbon to which theyare attached form a bicyclic structure:

wherein Q′ is the carbon shared with the piperidine ring, so that saidbicyclic structure together with said piperidine ring form a spirostructure; and

-   X, Y and Z are independently chosen from O; NR¹⁹; CR²³R²⁴ and S(O)n    wherein R¹⁹ is selected from hydrogen, C1₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,    trifluoromethyl, acyl, thioacyl and trifluoromethylsulfonyl, or R¹⁹    is a group R²⁰SO₂—, R²⁰OCO— or R²⁰SCO— wherein R²⁰ is C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkyl-C₁₋₆-alkyl or aryl, or R¹⁹ is a group R²¹R²²NCO—,    R²¹R²²NCS—, wherein R²¹ and R²² are independently hydrogen,    C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkyl-C₁₋₆-alkyl or aryl, wherein said aryl is    unsubstituted or substituted with one or more substituents selected    from C₁₋₆-alkyl or halogen; or R²¹ and R²² together with the N-atom    to which they are linked, form a pyrrolidinyl, piperidinyl or    perhydroazepinyl group; R²³ and R²⁴ are independently selected from    hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl,    heteroaryl, wherein said aryl is unsubstituted or substituted with    one or more substituents selected from C₁₋₆-alkyl or halogen, amino,    C₁₋₆-alkylamino, a group NR²⁵R²⁶ wherein R²⁵ and R²⁶ are    independently selected from C₁₋₆-alkyl or R²⁵ and R²⁶ together with    the N-atom to which they are linked, form a pyrrolidinyl,    piperidinyl, perhydroazepinyl or morpholinyl group,    C¹⁻⁶-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl,    di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,    trifluoromethyl, trifluoromethylsulfonyl, and C₁₋₆-alkylsulfonyl or    R²³ and R²⁴ together is oxo; and n is 0, 1 or 2; and a bond;    provided that no more than one of X, Y and Z may be a bond, and    provided that two adjacent groups X, Y or Z may not at the same time    be selected from O and S; and-   A¹, A², A³ and A⁴ are independently selected from N and CR²⁷ wherein    R²⁷ is hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, a    group NR²⁸R²⁹ wherein R²⁸ and R²⁹ are independently selected from    hydrogen and C₁₋₆-alkyl or R²⁸ and R²⁹ together with the N-atom to    which they are linked, form a pyrrolidinyl, piperidinyl,    perhydroazepinyl or morpholinyl group, C₁₋₆-alkylcarbonyl,    aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆alkyl)aminocarbonyl,    C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl,    difluoromethyl, fluoromethyl, trifluoromethylsulfonyl or    C₁₋₆-alkylsulfonyl; provided that only one of A¹, A², A³ and A⁴ may    be N.

In a preferred embodiment, the present invention relates to suchcompounds wherein X, Y and Z are selected from one of the combinations:X is oxygen, Y is a bond and Z is CR²³R²⁴; X is CR²³R²⁴, Y is a bond andZ is oxygen; X is NR¹⁹, Y is a bond and Z is CR²³R²⁴; X is CR²³R²⁴, Y isa bond and Z is NR¹⁹; X is CO, Y is a bond and Z is NR¹⁹; X is SO₂, Y isa bond and Z is NR¹⁹; X is SO, Y is a bond and Z is NR¹⁹; X is CR²³R²⁴,Y is a bond and Z is S; X is CR²³R²⁴, Y is a bond and Z is SO; X isCR²³R²⁴, Y is a bond and Z is SO₂; wherein R¹⁹ is hydrogen, acetyl ormethylsulfonyl and R²³ and R²⁴ are independently selected from hydrogen,methyl, isobutyl, cyclohexyl and 4-fluorophenyl.

In another preferred embodiment, the present invention relates to suchcompounds wherein —X—Y-Z- together form a group selected from:—O—CR²³R²⁴—, —CR²³R²⁴—O—, —NR¹⁹—CR²³R²⁴—, —CR²³R²⁴—NR¹⁹—, —CO—NR¹⁹—,—SO₂—NR¹⁹—, —SO—NR¹⁹—, —CR²³R²⁴—S—, —CR²³R²⁴—SO—, —CR²³R²⁴—SO₂—; whereinR¹⁹ is hydrogen, acetyl or methylsulfonyl tyl and R²³ and R²⁴ areindependently selected from hydrogen, methyl, isobutyl, cyclohexyl and4-fluorophenyl.

In another preferred embodiment, the present invention relates to suchcompounds wherein A³ is N or CR²⁷ wherein R²⁷ is halogen, cyano, nitro,a group NR²⁸R²⁹ wherein R²⁸ and R²⁹ are independently selected fromhydrogen and C₁₋₆-alkyl or R²⁸ and R²⁹ together with the N-atom to whichthey are linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl ormorpholinyl group, C₁₋₆-alkylcarbonyl, aminocarbonyl,C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl,trifluoromethylsulfonyl or C₁₋₆-alkylsulfonyl.

In another preferred embodiment, the present invention relates to suchcompounds wherein A¹, A², A³ and A⁴ are independently selected from CR²⁷wherein R²⁷ is as defined above.

In a more preferred embodiment, the present invention relates to suchcompounds wherein bicyclic structure described above is selected fromthe group comprising:

wherein R^(19′) is acetyl or methylsulfonyl, R^(23′) is hydrogen ormethyl, R^(27′) is hydrogen or fluoro, R^(27″) is hydrogen, fluoro,methyl or isopropyl, R^(27′″) is hydrogen, fluoro or trifluoromethyl.

In another embodiment, the present invention relates to such compoundswherein R⁹ and R¹⁰ together with the carbon to which they are attachedform a cyclic structure selected from the group comprising:

wherein Q′ is the carbon shared with the piperidine ring, so that saidcyclic structure together with said piperidine ring form a spirostructure

In yet another embodiment, the present invention relates to suchcompounds wherein R⁹ is benzyl, benzoyl, 2,3-dihydrobenzofuran-7-yl ormono- or bicyclic aryl or heteroaryl wherein each benzyl, benzoyl, arylor heteroaryl optionally is substituted with one or more substituentsselected from halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino,C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl,aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl,fluoromethyl and trifluoromethylsulfonyl.

In yet another embodiment, the present invention relates to suchcompounds wherein R⁹ is 2,3-dihydrobenzofuran-7-yl, benzyl or benzoylwherein said benzyl or benzoyl is unsubstituted or substituted with oneor more halogens in the phenyl groups, or R⁹ is mono- or bicyclic arylor heteroaryl selected from the group comprising phenyl, indolyl,pyridyl, thiophenyl and benzisoxazolyl, wherein each aryl or heteroaryloptionally is substituted with one or more substituents selected fromhalogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,di-(C₁₋₆alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyland trifluoromethylsulfonyl.

In a preferred embodiment, the present invention relates to suchcompounds wherein said mono- or bicyclic aryl or heteroaryl is selectedfrom the group comprising phenyl, indol-3-yl and benzisoxazol-3-ylwherein said phenyl, indol-3-yl or benzisoxazol-3-yl optionally issubstituted with one or more substituents selected from halogen, cyano,nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,C₁₋₆-alkylaminocarbonyl, di-(C1₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyland trifluoromethylsulfonyl.

In an even more preferred embodiment, the present invention relates tosuch compounds wherein said optional substituents are selected from thegroup comprising halogen, phenyl and methyl.

In yet another embodiment, the present invention relates to suchcompounds wherein Q is CR¹⁰ wherein R¹⁰ is selected from hydrogen,C₁₋₆-alkylcarbonyl, hydroxy, a group —NR³⁰COR³¹ wherein R³⁰ is hydrogenor C₁₋₆-alkyl and R³¹ is C₁₋₆-alkyl, a group —COOR¹⁶ wherein R¹⁶ isC₁₋₆-alkyl, or a group —CONR¹⁷R¹⁸ wherein R¹⁷ and R¹⁸ together with thenitrogen to which they are attached form a piperidinyl, piperazinyl ormorpholinyl, wherein said piperidinyl, piperazinyl and morpholinyl areunsubstituted or substituted with a C₁₋₆-alkyl.

In a preferred embodiment, the present invention relates to suchcompounds wherein R¹⁰ is selected from hydrogen, acetyl, hydroxy, agroup —NR³⁰COR³¹ wherein R³⁰ is hydrogen and R³¹ is methyl, a group—COOR¹⁶ wherein R¹⁶ is ethyl, or a group —CONR¹⁷R¹⁸ wherein R¹⁷ and R¹⁸together with the nitrogen to which they are attached form a piperidinylor a 4-methylpiperazinyl.

In another preferred embodiment, the present invention relates to suchcompounds wherein m is 2, 3 or 4, more preferred m is 2.

In yet another embodiment, the present invention relates to suchcompounds wherein R¹ is a group R¹¹CO—, R¹¹OCO— wherein R¹¹ isC₃₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, phenyl,phenyl-C₁₋₆-alkyl, pyridyl, furanyl, benzo[1,2,5]oxadiazolyl,quinoxalinyl, benzo[b]thiophenyl or naphthalenyl wherein each of saidC₃₋₆-alkyl, phenyl, pyridyl and furanyl groups independently areunsubstituted or substituted with one or more substituents selected fromthe group comprising halogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, phenyl andphenoxy wherein said phenyl and phenoxy independently are unsubstitutedor substituted with one halogen; or R¹ is a group R¹⁴R¹⁵NCO—, whereinR¹⁴ and R¹⁵ are independently hydrogen, C₁₋₆-alkyl, aryl, oraryl-C₁₋₆-alkyl, wherein each of said C₁₋₆-alkyl and aryl groupsindependently are unsubstituted or substituted with one substituentselected from the group comprising halogen and C₁₋₆-alkoxy.

In yet another embodiment, the present invention relates to suchcompounds wherein R² is hydrogen.

In yet another embodiment, the present invention relates to suchcompounds wherein R³ is hydrogen.

In yet another embodiment, the present invention relates to suchcompounds wherein R⁴ is hydrogen or methoxy.

In yet another embodiment, the present invention relates to suchcompounds wherein R⁵ is hydrogen or methoxy.

In yet another embodiment, the present invention relates to suchcompounds wherein R⁶ is hydrogen.

In yet another embodiment, the present invention relates to suchcompounds wherein R^(7a) and R^(7b) is hydrogen.

In yet another embodiment, the present invention relates to suchcompounds wherein R^(8a) and R^(8b) is hydrogen.

Preferred compounds of the invention are compounds number 1-209 asdisclosed in the experimental section as well as the compounds in thefollowing list:

-   1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,-   1-cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,-   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone,-   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,-   1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,-   1-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,-   1-cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,-   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,-   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone,-   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone,-   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone,-   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone,-   1-cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl)-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,-   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone,-   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-methanone,-   1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-methanone,-   1-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,-   1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,-   1-cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl)-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl)-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,-   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone,-   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-cyclopentyl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,-   1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,-   1-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,-   1-cyclopentyl-1-(1-(2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,-   N-[1-{2-[2-(1-(4-fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,-   1-cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-(4-fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-cyclopentyl-1-(1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-(4-fluorophenyl)-1-(1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,-   1-cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone,-   1-(1-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl)-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone,-   1-(4-fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,-   1-(4-fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,-   1-cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,    and-   1-cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone.

The compounds of the invention are NK₂ receptors antagonists having ahuman NK₂ binding affinity (IC50) of 5 μM or less, typically of 1 μM orless, preferably of 200 nM or less, more preferred of 50 nM or less andmost preferred of 10 μM or less.

Accordingly, the compounds of the invention are considered useful intreating a variety of CNS diseases such as depression, manic depression,bipolar disorder, dysthymia, mixed anxiety depression, generalisedanxiety disorder, social anxiety disorder, panic anxiety disorder, posttraumatic stress disorder, obsessive compulsive disorder, acute stressdisorder, phobia, pre-menstrual dysphoric disorder, psychosis andHuntington's disease as well as Parkinson's dementia, adjustmentdisorders, pain, emesis, migraine, epilepsia, obesity andcerebrovascular disease.

In particular, the compounds of the invention are considered useful inthe treatment of depression, manic depression, bipolar disorder,dysthymia, mixed anxiety depression, generalised anxiety disorder,social anxiety disorder, panic anxiety disorder, post traumatic stressdisorder, obsessive compulsive disorder, acute stress disorder, phobia,pre-menstrual dysphoric disorder and psychosis.

Thus, in another aspect, the present invention provides a pharmaceuticalcomposition comprising at least one compound of formula I as definedabove or a pharmaceutically acceptable acid addition salt thereof in atherapeutically effective amount and in combination with one or morepharmaceutically acceptable carriers or diluents.

In a further aspect, the present invention provides the use of acompound of formula I as defined above or an acid addition salt thereoffor the manufacture of a pharmaceutical preparation for the treatment ofthe above mentioned disorders.

The compounds of the general formula I may exist as optical isomersthereof and such optical isomers are also embraced by the invention.Throughout the specification and claims, reference to specific compoundsrefers to the racemates unless otherwise indicated.

The term C₁₋₆-alkyl refers to a branched or unbranched alkyl grouphaving from one to six carbon atoms inclusive, such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, and2-methyl-1-propyl. The terms C₁₋₈-alkyl, C₁₋₁₀-alkyl and C₁₋₁₂-alkyl,respectively, refer similarly to branched or unbranched alkyl grouphaving from one to eight, ten or twelve carbon atoms inclusive,respectively.

Similarly, C₂₋₆-alkenyl and C₂₋₆-alkynyl, respectively, designate suchgroups having from two to six carbon atoms, including one double bondand one triple bond, respectively, such as ethenyl, propenyl, butenyl,ethynyl, propynyl and butynyl.

The term C₃₋₈-cycloalkyl designates a monocyclic or bicyclic carbocyclehaving three to eight C-atoms, such as cyclopropyl, cyclopentyl,cyclohexyl, etc.

Halogen means fluoro, chloro, bromo or iodo.

As used herein, the term acyl refers to a formyl, C₁₋₆-alkylcarbonyl,arylcarbonyl, aryl-C₁₋₆-alkylcarbonyl, C₃₋₈-cycloalkylcarbonyl or aC₃₋₈-cycloalkyl-C₁₋₆-alkyl-carbonyl group, and the term thioacyl is thecorresponding acyl group, in which the carbonyl group is replaced with athiocarbonyl group.

The terms C₁₋₆-alkoxy, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkylsulfonyl,C₁₋₆-alkylamino, C₁₋₆-alkylcarbonyl, and the like, designate such groupsin which the C₁₋₆-alkyl and the C₃₋₈-cycloalkyl group are as definedabove.

The term aryl refers to a carbocyclic aromatic group, such as phenyl ornaphthyl, in particular phenyl.

The term heteroaryl refers to 5-membered monocyclic rings such as1H-tetrazolyl, 3H-1,2,3-oxathiazolyl, 3H-1,2,4-oxathiazolyl,3H-1,2,5-oxathiazolyl, 1,3,2-oxathiazolyl, 1,3,4-oxathiazolyl,1,4,2-oxathiazolyl, 3H-1,2,4-dioxazolyl, 1,3,2-dioxazolyl,1,4,2-dioxazolyl, 3H-1,2,3-dithiazolyl, 3H-1,2,4-dithiazolyl,1,3,2-dithiazolyl, 1,4,2-dithiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, 1H -1,2,3-triazolyl, 1H -1,2,4-triazolyl,isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1H-imidazolyl,1H-pyrazolyl, 1H-pyrrolyl, furanyl, thienyl, 1H-pentazole; 6-memberedmonocyclic rings such as 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl,1,2,5-oxathiazinyl, 4H-1,3,5-oxathiazinyl, 1,4,2-oxathiazinyl,1,4,3-oxathiazinyl, 1,2,3-dioxazinyl, 1,2,4-dioxazinyl,4H-1,3,2-dioxazinyl, 4H-1,3,5-dioxazinyl, 1,4,2-dioxazinyl,2H-1,5,2-dioxazinyl, 1,2,3-dithiazinyl, 1,2,4-dithiazinyl,4H-1,3,2-dithiazinyl, 4H-1,3,5-dithiazinyl, 1,4,2-dithiazinyl,2H-1,5,2-dithiazinyl, 2H-1,2,3-oxadiazinyl, 2H-1,2,4-oxadiazinyl,2H-1,2,5-oxadiazinyl, 2H-1,2,6-oxadiazinyl, 2H-1,3,4-oxadiazinyl,2H-1,3,5-oxadiazinyl, 2H-1,2,3-thiadiazinyl, 2H-1,2,4-thiadiazinyl,2H-1,2,5-thiadiazinyl, 2H-1,2,6-thiadiazinyl, 2H-1,3,4-thiadiazinyl,2H-1,3,5-thiadiazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, 2H-1,2-oxazinyl, 2H-1,3-oxazinyl, 2H-1,4-oxazinyl,2H-1,2-thiazinyl, 2H-1,3-thiazinyl, 2H-1,4-thiazinyl, pyrazinyl,pyridazinyl, pyrimidyl, pyridyl, 2H-pyranyl, 2H-thiinyl; and to bicyclicrings such as 3H-1,2,3-benzoxathiazolyl, 1,3,2-benzodioxazolyl,3H-1,2,3-benzodithiazolyl, 1,3,2-benzodithiazolyl, benzfurazanyl,1,2,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl,1H-benzotriazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, benzoxazolyl,1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzothiazolyl,1H-benzimidazolyl, 1H-indazolyl, 3H-1,2-benzoxathiolyl,1,3-benzoxathiolyl, 3H-2,1-benzoxathiolyl, 3H-1,2-benzodioxolyl,1,3-benzodioxolyl 3H-1,2-benzodithiolyl, 1,3-benzodithiolyl, 1H-indolyl,2H-isoindolyl, benzofuranyl, isobenzofuranyl, 1-benzothienyl,2-benzothienyl, 1H-2,1-benzoxazinyl, 1H-2,3-benzoxazinyl,2H-1,2-benzoxazinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl,2H-3,1-benzoxazinyl, 1H-2,1-benzothiazinyl, 1H-2,3-benzothiazinyl,2H-1,2-benzothiazinyl, 2H-1,3-benzothiazinyl, 2H-1,4-benzothiazinyl,2H-3,1-benzothiazinyl, cinnolinyl, phtalazinyl, quinazolinyl,quinoxalinyl, isoquinolyl, quinolyl, 1H-2-benzopyranyl,2H-1-benzopyranyl, 1H-2-benzothiopyranyl or 2H-1-benzothiopyranyl.

The acid addition salts of the compounds of the invention arepharmaceutically acceptable salts formed with non-toxic acids. Exemplaryof such organic salts are those with maleic, fumaric, benzoic, ascorbic,succinic, oxalic, bis-methylenesalicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,benzenesulfonic and theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline. Exemplary of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric and nitric acids.

The pharmaceutical compositions of this invention, or those which aremanufactured in accordance with this invention, may be administered byany suitable route, for example orally in the form of tablets, capsules,powders, syrups, etc., or parenterally in the form of solutions forinjection. For preparing such compositions, methods well known in theart may be used, and any pharmaceutically acceptable carriers, diluents,excipients or other additives normally used in the art may be used.

Conveniently, the compounds of the invention are administered in unitdosage form containing said compounds in an amount of about 0.01 to 100mg.

The total daily dose is usually in the range of about 0.05-500 mg, andmost preferably about 0.1 to 50 mg of the active compound of theinvention.

The compounds of the invention may be prepared as follows:

-   1) Alkylating a piperazine, piperidine or tetrahydropyridine of    formula III with an alkylating derivative of formula II:

wherein R¹-R⁹ and Q are as previously defined and L is a leaving groupsuch as e.g. halogen, mesylate or tosylate;

-   2) Reductive alkylation of an amine of formula III with a reagent of    formula IV:

wherein R¹-R⁹ and Q are as previously defined and E is an aldehyde or anactivated carboxylic acid;

-   3) Acylating an amine of formula V by the use of a carboxylic acid    and a coupling reagent, an activated ester, an acid chloride, an    isocyanate, carbamoyl chloride or by a two-step procedure by    treatment with phosgene followed by addition of an amine:

wherein R¹-R⁹ and Q are as previously defined, whereupon the compound offormula I is isolated as the free base or a pharmaceutically acceptableacid addition salt thereof.

The alkylation according to method 1) is conveniently performed in anorganic solvent such as a suitably boiling alcohol or ketone, preferablyin the presence of an organic or inorganic base (potassium carbonate,diisopropylethylamine or triethylamine) at reflux temperature.Alternatively, the alkylation can be performed at a fixed temperature,which is different from the boiling point, in one of the above-mentionedsolvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO), orN-methylpyrrolidin-2-one (NMP), preferably in the presence of a base.The alkylating agents of formula II can be prepared by methods analoguesto those described in the examples or can be synthesised by applyingmethods described in standard works such as Houben-Weyl, Methoden derorganischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag,Stuttgart; Organic Reactions, John Wiley & Sons, Inc. New York, namelyunder reaction conditions such as those which are known and suitable forsuch reactions. The amines of formula III are either commerciallyavailable or have been described in the literature or can be prepared bymethods analogues to those described in the literature e.g. Marxer etal. J. Org. Chem. 1975, 40, 1427, by Parham et al. J. Org. Chem. 1976,41, 2628 and by Bauer et al. J. Med. Chem. 1976, 19, 1315, Maligres etal. Tetrahedron 1997, 53, 10983, and by Cheng et al. Tet. Lett. 1997,38, 1497, Chen, Meng-Hsin; Abraham, John A. Tetrahedron Lett. 1996, 37,5233-5234 and Slade, P. D. et al. J. Med. Chem. 1998, 41, 1218-1235, orcan be synthesised by methods described in standard works such asHouben-Weyl, Methoden der organischen Chemie (Methods of OrganicChemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, JohnWiley & Sons, Inc. New York, namely under reaction conditions such asthose which are known and suitable for such reactions.

The reductive alkylation according to method 2) is performed by standardliterature methods or as described in standard works such asHouben-Weyl, Methoden der organischen Chemie (Methods of OrganicChemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, JohnWiley & Sons, Inc. New York, namely under reaction conditions such asthose which are known and suitable for such reactions. The reaction canbe performed in two steps, e.g. coupling of amines of formula III with areagent of formula IV by standard methods via the carboxylic acidchloride, activated esters or by the use of carboxylic acids incombination with a coupling reagents such as e.g. dicyclohexylcarbodiimide, followed by reduction of the resulting amide with lithiumaluminium hydride or alane. The carboxylic acids of formula IV areeither commercially available or can be prepared by methods analogues tothose described in the literature (e.g. Tet. Lett. 37, 1996, pp.5453-5456; Tet. Lett. 35, 1994, pp. 6567-6570; J. Med. Chem. 25, 1982,pp. 1235-1240; Synthesis 1987, pp. 474-477).

The acylation according to method 3) is conveniently performed bystandard methods via the carboxylic acid chloride, activated esters orby the use of carboxylic acids in combination with coupling reagentssuch as e.g. dicyclohexyl carbodiimide. When the acylating reagent iscarbamoyl chlorides or isocyanates, the acylation produces ureaderivatives. The urea derivatives can also be prepared by a two-stepprocedure consisting of treatment with phosgene followed by addition ofan amine.

The intermediate compounds of formula V are prepared as described inmethods 1) and 2), wherein R²-R⁹, Q, L and E are as previously defined,and R¹ is a protection group. This protection group may be chosen fromthose protection group generally used for protection of amino groups.Those skilled in the art will know to select appropriate protectiongroups and how to protect and deprotect the amines with these protectiongroups.

Experimental Section

Melting points were determined on a Büchi SMP-20 apparatus and areuncorrected. Analytical LC-MS data were obtained on a PE Sciex API 150EXinstrument equipped with IonSpray source and Shimadzu LC-8A/SLC-10A LCsystem. The LC conditions (C18 column 4.6×30 mm with a particle size of3.5 μm) were linear gradient elution withwater/acetonitrile/trifluoroacetic acid (90:10:0.05) towater/acetonitrile/trifluoroacetic acid (10:90:0.03) in 4 min at 2mL/min. Purity was determined by integration of the UV trace (254 nm).The retention times, R_(t), are expressed in minutes.

Mass spectra were obtained by an alternating scan method to givemolecular weight information. The molecular ion, MH+, was obtained atlow orifice voltage (5-20V) and fragmentation at high orifice voltage(100-200V).

Preparative LC-MS-separation was performed on the same instrument. TheLC conditions (C18 column 20×50 mm with a particle size of 5 μm) werelinear gradient elution with water/acetonitrile/trifluoroacetic acid(80:20:0.05) to water/acetonitrile/trifluoroacetic acid (5:95:0.03) in 7min at 22.7 mL/min. Fraction collection was performed by split-flow MSdetection.

¹H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500instrument or at 250.13 MHz on a Bruker AC 250 instrument. Deuteratedchloroform (99.8% D) or dimethyl sulfoxide (99.9% D) were used assolvents. TMS was used as internal reference standard. Chemical shiftvalues are expressed in ppm-values. The following abbreviations are usedfor multiplicity of NMR signals: s=singlet, d=doublet, tt=triplet,q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet,dq=double quartet, tt=triplet of triplets, m=multiplet. NMR signalscorresponding to acidic protons are generally omitted. For columnchromatography silica gel of type Kieselgel 60, 230-400 mesh ASTM wasused. For ion-exchange chromatography (SCX, 1 g, Varian Mega Bond Elut®,Chrompack cat. No. 220776) was used. Prior use of the SCX-columns waspre-conditioned with 10% solution of acetic acid in methanol (3 mL).

Preparation of Intermediates

Alkylating Reagents of the Formula II

1. (RS)-1-(2-Bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid-tert-butyl ester Tetrahydrosioquinolinic acid (10 g) was suspendedin tetrahydrofuran THF (100 mL). Triethyl amine (9.1 mL) anddi-tert-butyl dicarbonate (14.3 g) was added and the mixture stirred atroom temperature for 16 h. The mixture was concentrated in vacuo,redissolved in ethyl acetate (250 mL) and washed twice with and aqueous0.5 M KHSO₄-solution (200 mL), dried over magnesium sulphate andevaporated in vacuo to give1-carboxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester in quantitative yield as a clear oil which crystallised uponstanding. The protected amino acid was dissolved in dry tetrahydrofuranunder nitrogen, cooled to 0° C. and 1M borane in tetrahydrofuran (41.5mL) was added slowly under nitrogen during 15 min. The mixture waswarmed to room temperature and stirred for 1 h. Excess borane wascarefully destroyed by slow addition of 50 mL of a 1:1 mixture ofwater/tetrahydrofuran. The mixture was made alkaline to pH=12 byaddition of saturated potassium carbonate and extracted withdiethylether (2×50 mL). The combined organic phase were dried (magnesiumsulphate) and evaporated in vacuo to give1-(2-Hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester as a clear oil (8.4 g). The protected aminoalcohol wasdissolved in dry tetrahydrofuran (150 mL) together with triethylamine(5.6 mL) and cooled to 0° C. under nitrogen. Methanosulfonyl chloride(2.64 mL) in dry THF (30 mL) was added dropwise during 15 min and themixture was warmed to room temperature and stirred for 30 min. Afterfiltration and concentration in vacuo the clear oily residue wasdissolved in acetone (300 mL), lithium bromide (14.6 g) was added andthe mixture was heated to reflux for 1 h. The mixture was filtered,evaporated in vacuo and the product purified by column chromatography onsilicagel using as eluent ethyl acetate/heptane (1:1) and fractionscontaining the product was pooled and evaporated in vacuo to give(RS)-1-(2-Bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid-tert-butyl ester as a clear oil (8 g) which crystallised uponstanding.

The following compound was prepared in a similar way:

-   (RS)-1-(2-Bromo-ethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic    acid-tert-butyl ester    Piperidines of the Formula III

The piperidine-derivatives of formula III, wherein X is oxygen, Z isCR⁹R¹⁰, Y is a bond, A¹, A² and A⁴ are CH, A³ is CR¹¹, i.e.spiro[isobenzofuran-1(3H),4′-piperidines] are prepared according to themethods described by Marxer et al. J. Org. Chem. 1975, 40, 1427, byParham et al. J. Org. Chem. 1976, 41, 2628 and by Bauer et al. J. Med.Chem. 1976, 19, 1315.

The following compounds were prepared in a similar way:

-   6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine],-   6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine],-   6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine],-   6-trifluoromethyl-3-methylspiro[isobenzofuran-1(3H),4′-piperidine],-   5-methylspiro[isobenzofuran-1(3H),4′-piperidine],-   6-fluoro-3-isobutylspiro[isobenzofuran-1(3H),4′-piperidine],-   6-fluoro-3-cyclohexylspiro[isobenzofuran-1(3H),4′-piperidine] and-   6-fluoro-3-(4-fluorophenyl)spiro[isobenzofuran-1(3H),4′-piperidine]

The piperidine-derivatives of formula III, wherein X is CR⁹R¹⁰, Z isNR⁸, Y is a bond, A¹, A² and A⁴ are CH, A³ is CR¹¹ and R¹¹ is fluoro ortrifluoromethyl, are prepared according to the methods described byMaligres et al. Tetrahedron 1997, 53, 10983, and by Cheng et al. Tet.Lett. 1997, 38, 1497.

The following compound was prepared in a similar way:

-   1-Acetyl-5-fluoro-spiro[2,3-dihydro-1H-indol-3,4′-piperidine].

The piperidine-derivatives of formula III, wherein the X is CR⁹R¹⁰, Z isoxygen, Y is a bond, A¹, A² and A⁴ are CH, A³ is CR¹¹, i.e.2,3-dihydro-spiro(benzofuran-3,4′-piperidines), are prepared accordingto the methods described by Chen, Meng-Hsin; Abraham, John A.Tetrahedron Lett. 1996, 37, 5233-5234 and Slade, P. D. et al. J. Med.Chem. 1998, 41, 1218-1235.

The following compounds were prepared in a similar way:

-   2,3-Dihydro-5-fluorospiro[benzofiuran-3,4′-piperidine] and-   2,3-dihydro-5,6-difluorospiro[benzofuran-3,4′-piperidine]

The substituents R⁸-R¹¹ are introduced by applying suitably substitutedstarting compounds to methods analogous to the above mentioned.

Amines of the Formula V

An amine of formula V was prepared by the following procedure:

A mixture of an amine of formula III (1 mmol),(RS)-1-(2-Bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid-tert-butyl ester (1.3 mmol) and potassium carbonate (1.3 mmol) inacetonitrile (20 mL) were heated to 85° C. for 6 h. The mixture wascooled to room temperature and evaporated in vacuo to give an yellowoily residue. The product was redissolved in dichloromethane (10 mL) andanisole (0.26 mL) and trifluoroacetic acid (10 mL) were added and themixture stirred at room temperature for 90 min. The mixture wasevaporated in vacuo. The product was either purified by chromatographyor used directly in the next step without purification.

The following compounds were purified by chromatography before furtheruse:

-   (RS)-1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-1,2,3,4-tetrahydro-isoquinoline-   (RS)-1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-1,2,3,4-tetrahydroisoquinoline    Enantiomeric Forms of Amines of the Formula V-   Enantiomer 1 and enantiomer 2 of    N-(4-(3-Fluoro-phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-piperidin-4-yl}acetamide

RacemicN-{4-(3-fluoro-phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-piperidin-4-yl}acetamidewas subjected to resolution by chiral HPLC using a Gilson SF3supercritical fluid chromatography system equipped with chiralcelODcolumns (4.6 mm×25 cm for analytical and 10 mm×25 cm for preparativeruns). The particle size in the columns was 10 μm. A solution of theracemic compoundN-{4-(3-fluoro-phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-piperidin-4-yl)acetamide(1 g) in methanol (1 mL) was injected in 40 μL portions on a preparativecolumn. The column was eluted with carbondioxide-modifier (75:25). Themodifier was 2-propanol with diethylamine (0.5%) and trifluoracetic acid(0.5%). The flow was 18.9 mL/min at 20 Mpa. Fraction collection wastriggered by UV-detection (210 nM). The fractions containing theseparate products were pooled and evaporated in vacuo which gave theenantiomers. The first eluted enantiomer is called Enantiomer 1 and thesecond eluted is called Enantiomer 2 ofN-{4-(3-fluoro-phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-piperidin-4-yl}acetamide.The enantiomers were measured by HPLC to have an enantiomeric excesshigher than 95%.

The following enantiomers were prepared in a similar way:

-   Enantiomer 1 and enantiomer 2 of    N-(4-(phenyl)-1-[2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-piperidin-4-yl}acetamide

EXAMPLES Preparation of the Compounds of the Invention

The compounds of the present invention were prepared by one of twogeneral methods:

Method A: Alkylating a Piperidine of Formula III with an AlkylatingDerivative of Formula II:

A mixture of a piperidine of formula III (1 mmol),(RS)-1-(2-Bromo-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid-tert-butyl ester (1.3 mmol) and potassium carbonate (1.3 mmol) inacetonitrile (20 mL) were heated to 85° C. for 6 h. The mixture wascooled to room temperature and evaporated in vacuo. The product waspurified by chromatography either on silicagel using as eluentethylacetate/triethylamine (99:1) or by purified by HPLC. Fractionscontaining the product were pooled and evaporated in vacuo.

Method B: Acylating an Amine of Formula V by the Use of a CarboxylicAcid and a Coupling Reagent, an Activated Ester, an Acid Chloride or anIsocyanate:

An amine of formula V (prepared as described above; 1 mmol) andtriethylamine (5 mmol) were dissolved in anhydrous acetonitrile (10 mL).An appropriately substituted acid chloride (5 mmol) was added and thereaction mixture stirred at room temperature for 30 min. Methanol (0.5mL) was added to the reaction mixture followed by evaporation in vacuo.The product was purified by chromatography either on silicagel usingethylacetate/triethylamine (99:1) as eluent or by HPLC. Fractionscontaining the product were pooled and evaporated in vacuo andcharacterised by HPLC-UV-ELSD-MS. The measured HPLC-retention time, themeasured molecular mass and UV- and ELSD-purities are shown in table 1.

The following compounds were made by the methods indicated in table 1.Analytical data are shown in table 1.

Compound

-   1.    1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone-   2.    1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   3.    1-(2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic    acid phenethyl-amide-   4.    1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenylmethanone-   5.    1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-fluoro-phenyl)methanone-   6.    1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3-phenyl-propan-1-one-   7.    1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic    acid (3-chloro-propyl)amide-   8.    1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic    acid (2-methoxy-phenyl)amide-   9.    1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic    acid tert-butyl ester-   10.    3-Chloro-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2,2-dimethyl-propan-1-one-   12.    1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   13.    1-[2-(4-Chloro-phenoxy)-pyridin-3-yl]-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methano-   14.    1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic    acid tert-butyl ester-   15.    1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenylmethanone-   16.    1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-p-tolylmethanone-   17.    1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-methoxy-phenyl)methanone-   18.    1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   19.    1-(2-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   20.    1-(2-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   21.    1-(4-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   22.    1-(4-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   23.    1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic    acid phenethyl amide-   24.    1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-methoxy-phenyl)methanone-   25.    1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3-phenyl-propan-1-one-   26.    2-Ethyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one-   27.    1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-methoxy-phenyl)methanone-   28.    1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-phenylethanone-   29.    3-Cyclohexyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one-   30.    2-(4-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)ethanone-   31.    1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic    acid (3,4-dichloro-phenyl)amide-   32.    1-Cyclopropyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   33. 1-(1-{2-[6-Fluorospiro[isobenzofuran-1    (3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-pyridin-3-yl-methanone-   34.    1-[5-(4-Chloro-phenyl)-2-methyl-furan-3-yl]-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methano-   35.    2-(4-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)ethanone-   36.    1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-propan-1-one-   37.    1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic    acid (2-ethyl-phenyl)amide-   38.    N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide-   39.    1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidin-1′-yl]]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   40.    1-Cycloheptyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone-   41.    N-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl)acetamide-   42.    1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   43.    1-(4-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   44.    1-Cycloheptyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   45.    1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone-   46.    1-(4-Fluorophenyl)-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   47.    1-Cycloheptyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   48.    1-Cycloheptyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   49.    1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   50.    1-Cyclopentyl-1-{1-[spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone-   51.    1-Cyclopentyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   52.    1-(4-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   53.    1-(2-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   54.    1-Cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   55.    1-Cycloheptyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   56.    1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone-   57.    1-Cyclopentyl-1-(1-{2-[5-isopropylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   58.    N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide-   59.    1-Cycloheptyl-1-{1-[2-(4-phenylpiperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone-   60.    1-Cycloheptyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   61.    1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   62.    1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   63.    1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   64.    1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone-   65.    1-[1-(2-{2-[1-(4-Fluorophenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenylpiperidin-4-yl]-1-piperidin-1-yl-methanone-   66.    1-Cyclopentyl-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   67.    8-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one-   68.    1-Cycloheptyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   69.    1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]-1-(4-methyl-piperazin-1-yl)methanone-   70.    1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidine-4-carboxylic    acid ethyl ester-   71.    1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-ethanone-   72.    1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   73.    1-Cyclopentyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   74.    1-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)ethanone-   75.    1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   76.    1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone-   77.    1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-1-(4-fluoro-phenyl)methanone-   78.    1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-(4-methyl-piperazin-1-yl)methanone-   79.    1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cyclopentylmethanone-   80.    1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   81.    1-(4-Fluorophenyl)-1-(1-{2-[piro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   82.    1-Cyclopentyl-1-(1-{2-[4-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   83.    1-(2-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   84.    N-[4-(3-Fluoro-phenyl)-1-(2-{2-[1-(4-fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-piperidin-4-yl]-acetamide-   85.    1-(2-Fluorophenyl)-1-{1-[spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone-   86.    1-Cycloheptyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   87.    1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone-   88.    1-{1-[2-(4-Benzyl-piperidin-1-yl)-ethyl-3,4-dihydro-H-isoquinolin-2-yl}-1-cycloheptylmethanone-   89.    1-(2-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   90.    1-(1-{2-[(Chloro-trifluoromethyl-phenyl)-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone-   91.    1-(1-{2-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone-   92.    1-Cycloheptyl-1-(1-{2-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   93.    1-(1-{2-[4-(7-Chloro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cyclopentylmethanone-   94.    1-Cyclopentyl-1-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   95.    1-(1-{2-[4-(2,3-Dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone-   96.    N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide-   97.    1-(4-Fluoro-phenyl)-1-{1-[2-(4-phenyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone-   98.    1-(1-{2-[4-(6-Chloro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone-   99.    1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   100.    1-Cycloheptyl-1-{1-[spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl}methanone-   101.    N-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide-   102.    1-(1-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-fluoro-phenyl)methanone-   103.    1-cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   104.    1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidine-4-carboxylic    acid ethyl ester-   105.    1-(1-{2-[4-(4-Dimethylamino-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone-   106.    1-Cyclopentyl-1-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   107.    1-[1-(2-{2-[1-(4-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquiinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]ethanone-   108.    1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]ethanone-   109.    1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]-1-piperidin-1-yl-methanone-   110.    1-Cyclopentyl-1-{1-[2-(4-phenyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone-   111.    1-(2-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone-   112.    1-(4-Fluoro-phenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   113.    1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone-   114.    3,3-Dimethyl-[1-{2-[spiro(5-fluoro-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one-   115.    Cyclohexyl-[1-{2-[spiro(5-fluoro-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone-   116.    Cyclohexyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   117.    Cyclohexyl-[1-{2-[spiro(benzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone-   118.    Cyclohexyl-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   119.    N-{1-[2-(2-Cyclohexanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-phenyl-piperidin-4-yl}-acetamide-   120.    3,3-Dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one-   121.    Cyclohexyl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   122.    Cyclohexyl-(1-{2-[4-(4-dimethylamino-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   123.    3-Phenyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propanone-   124.    (1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl-methanone-   125.    2-Phenoxy-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-ethan-1-one-   126.    Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   127.    Cyclohexyl-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   128.    2-Propyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-pentan-1-one-   129.    2,2-Dimethyl-3-chlor-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one-   130.    Cyclohexyl-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   131.    3,3-Dimethyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one-   132.    Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   133.    2-Ethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one-   134.    2-Benzyloxy-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethan-1-one-   135.    Benzo[1,2,5]oxadiazol-5-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone-   136.    (1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl-methanone-   137.    1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one-   138.    3,5,5-Trimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-hexan-1-one-   139.    3,5,5-Trimethyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one-   140.    2-Phenoxy-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethan-1-one-   141.    (1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-(2,2-dichloro-cyclopropyl)-methanone-   142.    2-Benzyloxy-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-ethan-1-one-   143.    1-(1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one-   144.    1-(1-{2-[4-(2,3-Dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one-   145.    3,5,5-Trimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one-   146.    2,2-Dimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one-   147.    3-Cyclohexyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one-   148.    Furan-2-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone-   149.    N-(4-Phenyl-1-{2-[2-(3,5,5-trimethyl-hexanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-acetamide-   150.    Quinoxalin-2-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone-   151.    3-Cyclohexyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one-   152.    Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   153.    Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   154.    (Tetrahydro-pyran-4-yl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   155.    2-Propyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-pentan-1-one-   156.    2-Ethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one-   157.    3-Phenyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one-   158.    3,3-Dimethyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one-   159.    (1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(2,2-dichloro-cyclopropyl)-methanone-   160.    1,2,3,4-tetrahydro-naphthalene-2-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   161.    (4-Methylsulfanyl-phenyl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   162.    3,5,5-Trimethyl-1(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one-   163.    3-Phenyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one-   164.    Furan-2-yl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   165.    2-Benzyloxy-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone-   166.    1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-phenoxy-ethanone-   167.    Quinoxalin-2-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   168.    2,2-Dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one-   169.    (2,2-Dichloro-cyclopropyl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   170.    4-Methylsulfanyl-phenyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   171.    (2,2-Dichloro-cyclopropyl)-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   172.    1-(1-{2-[4-(4-Isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,5,5-trimethyl-hexan-1-one-   173.    2,2-Dichloro-cyclopropyl-(1-{2-[spiro(isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   174.    N-(4-Phenyl-1-{2-[2-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-acetamide-   175.    Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(4-chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone-   176.    N-(1-{2-[2-(3,3-Dimethyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-acetamide-   177.    3-Chloro-2,2-dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one-   178.    Tetrahydro-pyran-4-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one

The following compounds were made as enantiomers by method B startingfrom Enantiomer 2 of the corresponding amines of formula V. Analyticaldata are shown in table 1.

Compound

-   179.    N-(4-(3-Fluoro-phenyl)-1-{2-[2-(2-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide    (Enantiomer)-   180.    N-(4-(3-Fluoro-phenyl)-1-{2-[2-(2-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide    (Enantiomer)-   181.    N-[1-{2-[2-(4-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide    (Enantiomer)-   182.    N-[1-{2-[2-(4-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide    (Enantiomer)-   183.    N-[1-{2-[2-(4-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide    (Enantiomer)-   184.    N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-isopropyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide    (Enantiomer)-   185.    N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-methyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide    (Enantiomer)-   186.    N-[1-{2-[2-(3-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide    (Enantiomer)-   187.    N-[1-{2-[2-(2-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide    (Enantiomer)-   188.    N-(1-{2-[2-(4-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide    (Enantiomer)-   189.    N-(1-{2-[2-(2,4-Dichloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide    (Enantiomer)-   190.    N-[1-{2-[2-(2,4-Dichloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide    (Enantiomer)-   191.    N-[1-{2-[2-(Benzo[1,2,5]oxadiazole-5-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide    (Enantiomer)-   192.    N-(4-(3-Fluoro-phenyl)-1-{2-[2-(naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide    (Enantiomer)-   193.    N-[1-[2-(2-Cyclopentanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide    (Enantiomer)-   194.    N-(1-{2-[2-(4-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide    (Enantiomer)-   195.    N-[1-{2-[2-(Benzo[b]thiophene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide    (Enantiomer)-   196.    N-[1-{2-[2-(6-Fluoro-4H-benzo[1,3]dioxine-8-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide    (Enantiomer)-   197.    N-[1-{2-[2-(3-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide    (Enantiomer)-   198.    N-[1-{2-[2-(2-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide    (Enantiomer)-   199.    N-(1-{2-[2-(4-Methyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide    (Enantiomer)-   200.    N-[1-{2-[2-(2-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide    (Enantiomer)-   201.    N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide    (Enantiomer)-   202.    N-(1-{2-[2-(3-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl}-4-phenyl-piperidin-4-yl)acetamide    (Enantiomer)-   203.    N-(1-{2-[2-(4-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide    (Enantiomer)-   204.    N-{1-[2-(2-Cycloheptanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-phenyl-piperidin-4-yl}-acetamide    (Enantiomer)-   205.    N-(1-{2-[2-(3-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide    (Enantiomer)-   206.    2-N-(4-(3-Fluoro-phenyl)-1-{2-[2-(3-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide    (Enantiomer)-   207.    N-(4-(3-Fluoro-phenyl)-1-{2-[2-(thiophene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide    (Enantiomer)-   208.    N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-pyrazol-1-yl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide    (Enantiomer)-   209.    N-(1-{2-[2-(Naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide    (Enantiomer)

TABLE 1 Measured molecular mass (M + H⁺), measured HPLC-retention time(RT, min) and UV- and ELSD-purities (%) and synthesis method. RTUV-purity ELSD-purity Synthesis compound M + H⁺ min. (%) (%) method 1500.3 2.34 84.41 100 B 2 474.4 2.38 83.5 100 B 3 496.3 2.45 75.89 100 B4 481.9 2.29 83.81 100 B 5 500.2 2.29 83.54 100 B 6 510 2.46 84.14 100 B7 497.4 2.29 100 100 B 8 525.4 2.40 89.67 100 B 9 478.2 2.20 75.37 99.26A 10 497.1 2.36 75.37 99.26 B 12 463 2.31 100 100 B 13 598.1 2.45 93.85100 B 14 467 2.43 73.81 96.61 B 15 471.2 2.21 93.09 100 B 16 485 2.3486.3 100 B 17 501.2 2.27 94.08 100 B 18 491.1 2.54 100 100 B 19 488.92.22 84.77 100 B 20 504.9 2.27 77.86 100 B 21 489.2 2.25 80.99 100 B 22505.1 2.39 85.64 100 B 23 514.2 2.42 79.04 100 B 24 501.3 2.25 83.9399.53 B 25 499.1 2.42 91.88 100 B 26 465.1 2.34 97.12 100 B 27 501.12.25 82.81 100 B 28 485.2 2.27 72.97 100 B 29 505.2 2.73 71.89 100 B 30502.8 2.31 74.17 100 B 31 554.2 2.60 95.47 100 B 32 435.2 2.06 86.69 100B 33 472 1.80 95.32 100 B 34 585 2.81 96.53 100 B 35 519 2.44 89.59 100B 36 437.3 2.13 91.14 100 B 37 514.2 2.40 85.04 100 B 38 520.3 2.2971.77 76.11 B 39 477.4 2.43 91.78 100 B 40 514.3 2.33 91.25 99.32 B 41502.3 2.35 70.93 83.59 B 42 551.3 2.44 90.64 100 B 43 503.1 2.37 74.38100 B 44 550.1 2.50 73.67 95.11 B 45 528.3 2.44 93.37 79.93 B 46 548.22.22 94.88 100 B 47 498.3 2.66 74.25 96.35 B 48 513.3 2.77 100 97.34 B49 537.1 2.33 89.23 100 B 50 486.4 2.12 99.47 100 B 51 522.3 2.29 100100 B 52 563.1 2.27 72.61 100 B 53 489.2 2.23 76.61 100 B 54 473.6 2.5170.49 82.63 B 55 565.3 2.55 72.19 100 B 56 479.2 2.74 74.67 83.39 B 57487.3 2.66 82.69 99.27 B 58 492.2 2.08 85.05 100 B 59 445.5 2.58 70.2373.14 B 60 505.2 2.65 71.04 76.63 B 61 485.1 2.57 88.72 100 B 62 523.42.23 100 100 B 63 549.3 2.19 93.44 100 B 64 502.4 2.29 91.44 100 B 65554.3 2.38 93.61 100 B 66 435.3 2.38 72.75 93.86 B 67 515.3 2.51 77.6778.14 B 68 601.3 2.63 81.38 97.64 B 69 569.3 1.65 76.77 88.30 B 70 517.32.67 79.03 86.76 B 71 487.4 2.50 72.35 95.17 B 72 573.5 2.42 90.45 100 B73 470.4 2.45 83.20 100 B 74 459.4 2.27 92.31 100 B 75 599.3 2.36 96.2698.55 B 76 477.2 2.40 100 93.03 B 77 491.3 2.51 86.66 73.72 B 78 631.51.84 75.78 100 B 79 451.1 2.50 86.14 100 B 80 511.1 2.48 100 100 B 81471.3 2.23 92.66 100 B 82 463.3 2.36 100 100 B 83 563.1 2.24 90.29 100 B84 518.2 2.03 95.48 100 B 85 512.2 2.02 94.94 88.11 B 86 610.5 2.4194.60 98.31 B 87 616.2 2.56 89.81 100 B 88 459.3 2.69 71.44 73.94 B 89599.2 2.33 91.53 100 B 90 623.4 2.65 87.37 98.35 B 91 555.3 2.44 89.31100 B 92 503.2 2.90 71.70 70.84 B 93 490.2 2.48 100 100 B 94 459.2 2.4283.29 100 B 95 485.3 2.33 94.29 100 B 96 580.5 2.22 96.44 100 B 97 443.22.25 98.80 100 B 98 516 2.42 90.05 100 B 99 461.2 2.29 100 100 B 100574.4 2.26 99.42 100 B 101 474.4 2.02 100 100 B 102 502.3 2.23 94.60 100B 103 533.1 2.41 87.36 97.35 B 104 489.4 2.46 79.39 100 B 105 486.4 1.6588.94 100 B 106 459.5 2.74 81.14 100 B 107 485.4 2.21 94.86 100 B 108485 2.16 70.08 70.13 B 109 554.4 2.34 70.00 74.91 B 110 417.2 2.35 92.41100 B 111 549.4 2.14 95.35 100 B 112 507.5 2.45 88.27 98.43 B 113 489.62.33 89.20 97.90 B 114 464.6 2.39 97.56 100 B 115 476.6 2.44 97.18 100 B116 472.7 2.53 98.22 100 B 117 458.6 2.40 86.63 100 B 118 483.7 2.5399.38 100 B 119 487.7 2.13 95.52 100 B 120 486.6 2.62 94.23 100 B 121498.6 2.66 98.51 100 B 122 473.7 1.75 94.26 100 B 123 498.6 2.44 97.66100 A 124 609.1 2.54 97.77 100 B 125 500.6 2.32 93.9 98.82 B 126 508.62.37 98.82 100 B 127 472.7 2.83 95.08 100 B 128 492.7 2.63 97.33 100 B129 485 2.29 94.23 99.4 B 130 472.7 2.52 95.96 100 B 131 460.7 2.4996.36 100 B 132 534.6 2.48 94.21 99.15 B 133 486.6 2.58 86.65 100 B 134510.7 2.41 75.55 96.08 B 135 512.6 2.29 98.04 100 B 136 465.1 2.58 96.36100 B 137 453.1 2.54 97.52 100 B 138 506.7 2.78 98.11 100 B 139 502.72.88 77.28 94.4 B 140 496.6 2.39 97.44 100 B 141 491.9 2.44 99.44 99.2 B142 514.6 2.34 91.48 98.85 B 143 597.1 2.49 97.94 100 B 144 460.7 2.4995.22 100 B 145 528.7 2.98 98.91 100 B 146 450.6 2.28 100 100 B 147526.7 2.92 96.57 99.25 B 148 460.5 2.10 96.13 99.34 B 149 517.8 2.5099.13 100 B 150 522.6 2.26 92.92 99.26 B 151 504.7 2.73 97.79 100 B 152508.6 2.33 99.37 100 B 153 519.6 2.33 99.06 100 B 154 500.6 2.19 96 99.4B 155 514.7 2.85 93.87 100 B 156 464.6 2.36 91.14 100 B 157 520.6 2.6494.34 99.05 B 158 471.7 2.51 97.9 100 B 159 635.9 2.39 96.68 98.58 B 160520.7 2.69 92.98 99.42 B 161 538.7 2.62 97.24 98.81 B 162 513.8 2.8895.64 100 B 163 494.7 2.52 98.25 100 B 164 482.5 2.32 91.14 100 B 165521.7 2.41 93.78 100 B 166 489.1 2.45 97.97 100 B 167 518.7 2.34 87.5897.31 B 168 472.6 2.50 94.41 99.01 B 169 525.4 2.52 98.4 98.78 B 170512.7 2.50 98.1 99.2 B 171 499.5 2.37 98.66 99.01 B 172 502.8 3.15 96.92100 B 173 485.5 2.28 86.08 99.43 B 174 535.7 2.32 89.96 99.01 B 175 5012.42 98.67 100 B 176 475.7 2.09 97.47 100 B 177 507 2.52 90.73 100 B 178478.6 1.94 91.92 100 B 179 530.3 2.01 89.59 99.31 B 180 550.2 2.32 96.4298.14 B 181 534.2 2.15 99.1 100 B 182 578.2 2.18 99.05 100 B 183 518.22.00 98.42 99.38 B 184 542.4 2.34 93.23 99.9 B 185 514.4 2.09 99.41 100B 186 534.2 2.11 98.69 100 B 187 578.3 2.04 71.31 100 B 188 562.2 2.1395.59 100 A 189 550.2 2.22 88.21 95.21 B 190 568.4 2.22 86.21 98.71 B191 542.4 2.03 99.09 100 B 192 550.2 2.17 97.37 100 B 193 492.3 2.0781.75 100 B 194 516.3 2.09 96.4 100 B 195 556.3 2.15 99.36 99.89 B 196576.3 2.03 96.774 100 B 197 580.4 2.14 98.59 100 B 198 518.2 1.95 82.8199.74 B 199 496.2 2.15 91.36 99.03 B 200 534.2 2.01 79.14 99.08 B 201530.3 2.01 99.08 100 B 202 516.3 2.16 94.57 98.33 B 203 500.5 1.97 96.4100 B 204 502.4 2.25 88.94 100 B 205 562.1 2.20 93.75 96.46 B 206 530.32.00 98.7 100 B 207 506.2 1.92 98.2 100 B 208 566.4 1.99 98.45 100 B 209532.2 2.21 93.74 98.44 BPharmacological Testing

The compounds of the invention were tested in a well-recognised andreliable test. The test was as follows:

Inhibition of Binding of ¹²⁵I-NKA to Human NK2 Receptors

The compounds of the invention have been found to potently inhibit thebinding of ¹²⁵I-NKA to the human NK2 receptor.

By this method, the inhibition by drugs of the binding of ¹²⁵I-NKA tomembranes of human cloned NK2 receptors expressed in CHO-cells isdetermined in vitro.

Briefly, the affinity of the compounds was measured by their ability todisplace ¹²⁵I-NKA, by incubating hNK2 expressing CHO membranes withcompound and radioligand at room temperature for 60 minutes. Incubationwas terminated by rapid filtration through GF/C filters, and filterswere counted in a Wallac Trilux Scintillation Counter. The IC50 valuesfor the compounds No. 1-209, exemplified above, was determined to be 200nM or less. For the majority of the compounds the IC50 values were 50 nMor less, and for a large group of the compounds the IC50 values were 10nM or less.

FORMULATION EXAMPLES

The pharmaceutical formulations of the invention may be prepared byconventional methods in the art.

For example: Tablets may be prepared by mixing the active ingredientwith ordinary adjuvants and/or diluents and subsequently compressing themixture in a conventional tabletting machine. Examples of adjuvants ordiluents comprise: Corn starch, potato starch, talcum, magnesiumstearate, gelatine, lactose, gums, and the like. Any other adjuvants oradditives usually used for such purposes such as colourings,flavourings, preservatives etc. may be used provided that they arecompatible with the active ingredients.

Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to thedesired volume, sterilising the solution and filling it in suitableampoules or vials. Any suitable additive conventionally used in the artmay be added, such as tonicity agents, preservatives, antioxidants, etc.

Typical examples of recipes for the formulation of the invention are asfollows:

-   1) Tablets containing 5.0 mg of a compound of the invention    calculated as the free base:

Compound 1a or 1b 5.0 mg Lactose 60 mg Maize starch 30 mgHydroxypropylcellulose 2.4 mg Microcrystalline cellulose 19.2 mgCroscarmellose Sodium Type A 2.4 mg Magnesium stearate 0.84 mg

-   2) Tablets containing 0.5 mg of a compound of the invention    calculated as the free base:

Compound 1a or 1b 0.5 mg Lactose 46.9 mg Maize starch 23.5 mg Povidone1.8 mg Microcrystalline cellulose 14.4 mg Croscarmellose Sodium Type A1.8 mg Magnesium stearate 0.63 mg

-   3) Syrup containing per millilitre:

Compound 1a or 1b 25 mg Sorbitol 500 mg Hydroxypropylcellulose 15 mgGlycerol 50 mg Methyl-paraben 1 mg Propyl-paraben 0.1 mg Ethanol 0.005mL Flavour 0.05 mg Saccharin sodium 0.5 mg Water ad 1 mL

-   4) Solution for injection containing per millilitre:

Compound 1a or 1b 0.5 mg Sorbitol 5.1 mg Acetic Acid 0.05 mg Saccharinsodium 0.5 mg Water ad 1 mL

1. A compound of formula I

wherein R¹ is R¹¹CO—, R¹¹CS—, R¹¹SO₂—, R¹¹OCO—, R¹¹SCO— orR¹¹CO—CR¹²R¹³— wherein R¹¹ is C₁₋₁₂-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆alkyl, aryl, aryl-C₁₋₆-alkyl,heteroaryl, heteroaryl-C₁₋₆-alkyl, tetrahydropyranyl,1,2,3,4-tetrahydronaphtalenyl, or 4H-benzo[1,3]dioxinyl optionallysubstituted with halogen, wherein each of said C₁₋₆-alkyl, aryl,heteroaryl and C₃₋₈-cycloalkyl groups independently are unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of halogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, aryl-C₁₋₆-alkoxy,C₁₋₆-alkylsulfanyl, aryl and aryloxy, wherein said aryl and aryloxyindependently are unsubstituted or substituted with one or more halogen;and R¹² and R¹³ independently are hydrogen or C₁₋₆-alkyl; or R¹ isR¹⁴R¹⁵NCO— or R¹⁴R¹⁵NCS—, wherein R¹⁴ and R¹⁵ each are independentlyhydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl or aryl-C₁₋₆-alkyl, wherein each ofsaid C₁₋₆-alkyl, aryl and C₃₋₈-cycloalkyl groups independently areunsubstituted or substituted with one or more substituents selected fromthe group consisting of halogen, C₁₋₆-alkyl and C₁₋₆-alkoxy; or R¹⁴ andR¹⁵, taken together with the N-atom to which they are linked, form apyrrolidinyl, piperidinyl or perhydroazepinyl group; R² is hydrogen,trifluoromethyl or C₁₋₆-alkyl; R³-R⁶, R^(7a), R^(7b), R^(8a) and R^(8b)each are independently hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl,aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl,trifluoromethylsulfonyl or C₁₋₆-alkylsulfonyl; m is 2-6; R⁹ is benzyl,benzoyl, 2,3-dihydrobenzofuranyl, mono- or bicyclic aryl, or heteroarylwherein each benzyl, benzoyl, aryl or heteroaryl optionally issubstituted with one or more substituents selected from halogen, cyano,nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyland trifluoromethylsulfonyl; Q is C, N or CR¹⁰; wherein R¹⁰ is hydrogen,halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl,trifluoromethylsulfonyl, —NR³⁰COR³¹ wherein R³⁰ is hydrogen orC₁₋₆-alkyl and R³¹ is C₁₋₆-alkyl, —COOR¹⁶ wherein R¹⁶ is hydrogen orC₁₋₆-alkyl, or —CONR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ each are independentlyhydrogen or C₁₋₆-alkyl; or R¹⁷ and R¹⁸, taken together with the nitrogento which they are attached, form a piperidinyl, piperazinyl ormorpholinyl group, wherein said piperidinyl, piperazinyl and morpholinylgroup is unsubstituted or substituted with a C₁₋₆-alkyl; or when Q isCR¹⁰, R⁹ and R¹⁰, taken together with a carbon to which they areattached, form a cyclic structure selected from the group consisting of:

wherein Q′ is a carbon shared with a piperidine ring whereby said cyclicstructure together with said piperidine ring forms a spiro structure;and X, Y, and Z each are independently O, NR¹⁹, CR²³R²⁴, S(O)_(n) or abond, wherein: R¹⁹ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆-alkyl, trifluoromethyl, acyl,thioacyl or trifluoromethylsulfonyl; R¹⁹ is R²⁰SO₂—, R²⁰OCO— or R²⁰SCO—,wherein R²⁰ is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl or aryl; or R¹⁹ is R²¹R²²NCO— or R²¹R²²NCS—,wherein R²¹ and R²² each are independently hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,or aryl, wherein said aryl is unsubstituted or substituted with one ormore substituents selected from C₁₋₆-alkyl or halogen; or R²¹ and R²²,taken together with the N-atom to which they are linked, form apyrrolidinyl, piperidinyl or perhydroazepinyl group; and R²³ and R²⁴each are independently hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,aryl or heteroaryl, wherein said aryl is unsubstituted or substitutedwith one or more substituents selected from C₁₋₆-alkyl, halogen, amino,C₁₋₆-alkylamino, or NR²⁵R²⁶, wherein R²⁵ and R²⁶ each are independentlyC₁₋₆-alkyl, C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl,di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,trifluoromethyl, trifluoromethylsulfonyl or C₁₋₆-alkylsulfonyl; or R²⁵and R²⁶, taken together with the N-atom to which they are linked, form apyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group; or R²³and R²⁴, taken together, form an oxo group; and n is 0, 1 or 2; providedthat no more than one of X, Y and Z may be a bond, and provided that twoadjacent X, Y or Z groups may not at the same time be O and S; and A¹,A², A³ and A⁴ each are independently N or CR²⁷, wherein R²⁷ is hydrogen,halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkylcarbonyl,aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl,fluoromethyl, trifluoromethylsulfonyl, C₁₋₆-alkylsulfonyl, amino, orNR²⁸R²⁹, wherein R²⁸ and R²⁹ each are independently hydrogen orC₁₋₆-alkyl; or R²⁸ and R²⁹, taken together with the N-atom to which theyare linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl ormorpholinyl group; provided that only one of A¹, A², A³ and A⁴ may be N;and provided that a dotted line emanating from Q is a bond when Q is C,and no bond when Q is CR¹⁰ or N; or a pharmaceutically acceptable acidaddition salt thereof.
 2. A compound according to claim 1, wherein Q isCR¹⁰, and R⁹ and R¹⁰, taken together with the carbon to which they areattached, form a bicyclic structure as shown in formula 1):

wherein Q′ is a carbon shared with a piperidine ring whereby saidbicyclic structure together with said piperidine ring form a spirostructure; and X, Y and Z each are independently O, NR¹⁹, CR²³R²⁴,S(O)_(n) or a bond, wherein R¹⁹ is hydrogen, C1₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,trifluoromethyl, acyl, thioacyl or trifluoromethylsulfonyl; R¹⁹ isR²⁰SO₂—, R²⁰OCO— or R²⁰SCO—, wherein R²⁰ is C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, or aryl; orR¹⁹ is R²¹R²²NCO— or R²¹R²²NCS—, wherein R²¹ and R²² each areindependently hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, or aryl, wherein said arylis unsubstituted or substituted with one or more substituents selectedfrom C₁₋₆-alkyl or halogen; or R²¹ and R²², taken together with theN-atom to which they are linked, form a pyrrolidinyl, piperidinyl, orperhydroazepinyl group; and R²³ and R²⁴ each are independently hydrogen,halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl, or heteroaryl,wherein said aryl is unsubstituted or substituted with one or moresubstituents selected from C₁₋₆-alkyl, halogen, amino, C₁₋₆-alkylamino,or NR²⁵R²⁶, wherein R²⁵ and R²⁶ each are independently C₁₋₆-alkyl,C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl,di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,trifluoromethyl, trifluoromethylsulfonyl or C₁₋₆-alkylsulfonyl; or R²⁵and R²⁶, taken together with the N-atom to which they are linked, form apyrrolidinyl, piperidinyl, perhydroazepinyl, or morpholinyl group; orR²³ and R²⁴, taken together form an oxo group; and n is 0, 1 or 2;provided that no more than one of X, Y and Z may be a bond, and providedthat two adjacent X, Y or Z groups may not at the same time be O and S;and A¹, A², A³ and A⁴ each are independently N CR²⁷, wherein R²⁷ ishydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkylcarbonyl,aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di- (C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkoxy, C₁₋₆-alkythio, hydroxy, trifluoromethyl, difluoromethyl,fluoromethyl, trifluoromethylsulfonyl, C₁₋₆-alkylsulfonyl, amino, orNR²⁸R²⁹, wherein ²⁸ and R²⁹ each are independently hydrogen orC₁₋₆-alkyl; or R²⁸ and R²⁹, taken together with the N-atom to which theyare linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl ormorpholinyl group provided that only one of A¹, A², A³ and A⁴ may be N.3. A compound according to claim 2, wherein X, Y and Z are one of thefollowing combinations: X is oxygen, Y is a bond and Z is CR²³R²⁴; X isCR²³R²⁴, Y is a bond and Z is oxygen; X is NR¹⁹, Y is a bond and Z isCR²³R²⁴; X is CR²³R²⁴, Y is a bond and Z is NR¹⁹; X is CO, Y is a bondand Z is NR¹⁹; X is SO₂, Y is a bond and Z is NR¹⁹; X is SO, Y is a bondand Z is NR¹⁹; X is CR²³R²⁴, Y is a bond and Z is S; X is CR²³R²⁴, Y isa bond and Z is SO; or X is CR²³R²⁴, Y is a bond and Z is SO₂, whereinR¹⁹ is hydrogen, acetyl or methylsulfonyl; and R²³ and R²⁴ each areindependently hydrogen, methyl, isobutyl, cyclohexyl or 4-fluorophenyl.4. A compound according to claim 2, wherein X,Y, and Z, taken togetherform a group selected from: —O—CR²³R²⁴—, —CR²³R²⁴—O—, —NR¹⁹—CR²³R²⁴—,—CR²³R²⁴—NR¹⁹—, —CO—NR¹⁹—, —SO₂—NR¹⁹—, —SO—NR¹⁹—, —CR²³R²⁴—S—,—CR²³R²⁴—SO—, and —CR²³R²⁴—SO₂—, wherein R¹⁹ is hydrogen, acetyl ormethylsulfonyl; and R²³ and R²⁴ each are independently hydrogen, methyl,isobutyl, cyclohexyl or 4-fluorophenyl.
 5. A compound according to claim2 wherein A³ is N or CR²⁷, wherein R²⁷ is halogen, cyano, nitro ,C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl,di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, hydroxy, trifluoromethyl,difluoromethyl, fluoromethyl, trifluoromethylsulfonyl,C₁₋₆-alkylsulfonyl, or NR²⁸R²⁹, wherein R²⁸ and R²⁹ each areindependently hydrogen or C₁₋₆-alkyl; or R²⁸ and R²⁹, taken togetherwith the N-atom to which they are linked, form a pyrrolidinyl,piperidinyl, perhydroazepinyl or morpholinyl group.
 6. A compoundaccording to claim 2, wherein A¹, A², A³and A⁴are each independentlyCR²⁷, wherein R²⁷ is hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalky-C₁₋₆-alkyl,C₁₋₆-alkylthio, amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,C₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyl,trifluoromethylsulfonyl, C₁₋₆-alkylsulfonyl, amino, or NR²⁸R²⁹, whereinR²⁸ and R²⁹ each are independently hydrogen or C₁₋₆-alkyl; or R²⁸ andR²⁹, taken together with the N-atom to which they are linked, form apvrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group;provided that only one of A¹, A², A³ and A⁴ may be N.
 7. A compoundaccording to claim 2, wherein said bicyclic structure is selected fromthe group consisting of:

wherein R^(19′) is acetyl or methylsulfonyl; R^(23′) is hydrogen ormethyl; R^(27′) is hydrogen or fluoro; R^(27″) is hydrogen, fluoro,methyl or isopropyl; and R^(27′″) is hydrogen, fluoro ortrifluoromethyl.
 8. A compound according to claim 1 wherein R⁹ and R¹⁰,taken together with a carbon to which they are attached, form a cyclicstructure selected from the group consisting of:

wherein Q′ is a carbon shared with a piperidine ring whereby said cyclicstructure together with said piperidine ring form a spiro structure. 9.A compound according to claim 1, wherein R⁹ is benzyl, benzoyl,2,3-dihydrobenzofuran-7-yl, mono- or bicyclic aryl, or heteroaryl,wherein each benzyl, benzoyl, aryl or heteroaryl optionally issubstituted with one or more substituents selected from halogen, cyano,nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyland trifluoromethylsulfonyl.
 10. A compound according to claim 9,wherein R⁹ is 2,3-dihydrobenzofuran-7-yl, benzyl or benzoyl, whereinsaid benzyl or benzoyl is unsubstituted or substituted with one or morehalogens; or R⁹ is mono- or bicyclic aryl or heteroaryl selected fromthe group consisting of phenyl, indolyl, pyridyl, thiophenyl andbenzisoxazolyl, wherein each aryl or heteroaryl optionally issubstituted with one or more substituents selected from halogen, cyano,nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C p6-alkylamino,di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyland trifluoromethylsulfonyl.
 11. A compound according to claim 10,wherein said mono- or bicyclic aryl or heteroaryl is selected from thegroup consisting of phenyl, indol-3-yl and benzisoxazol-3-yl, whereinsaid phenyl, indol-3-yl or benzisoxazol-3-yl optionally is substitutedwith one or more substituent selected from halogen, cyano, nitro,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl, fluoromethyland trifluoromethylsulfonyl.
 12. A compound according to claim 11,wherein said optional one or more substituent is selected from the groupconsisting of halogen, phenyl and methyl.
 13. A compound according toclaim 9, wherein Q is CR¹⁰, wherein R¹⁰ is hydrogen, C₁₋₆-alkylcarbonyl,hydroxy, —NR³⁰COR³¹, wherein R³⁰ is hydrogen or C₁₋₆-alkyl and R³¹ isC₁₋₆-alkyl, —COOR¹⁶, wherein R¹⁶ is C₁₋₆-alkyl; or —CONR¹⁷ R¹⁸, whereinR¹⁷ and R¹⁸, taken together with the nitrogen to which they areattached, form a piperidinyl, piperazinyl or morpholinyl group, whereinsaid piperidinyl, piperazinyl and morpholinyl group is unsubstituted orsubstituted with a C₁₋₆-alkyl.
 14. A compound according to claim 13,wherein R¹⁰ is hydrogen, acetyl, hydroxy, —NR³⁰COR³¹, wherein R³⁰ ishydrogen and R³¹ is methyl, —COOR¹⁶, wherein R¹⁶ is ethyl; or—CONR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸, taken together with the nitrogen towhich they are attached, form a piperidinyl or a 4-methylpiperazinylgroup.
 15. A compound according to claim 1, wherein m is 2, 3 or
 4. 16.A compound according to claim 15 wherein m is
 2. 17. A compoundaccording claim 1, wherein R¹ is R¹¹CO— or R¹¹OCO—, wherein R¹¹ isC₃₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, phenyl,phenyl-C₁₋₆-alkyl, pyridyl, furanyl, benzo[1,2,5]oxadiazolyl,quinoxalinyl, benzo[b]thiophenyl or naphthalenyl, wherein each of saidC₃₋₆-alkyl, phenyl, pyridyl and furanyl groups independently areunsubstituted or substituted with one or more substituents selected fromthe group consisting of halogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, phenyl andphenoxy, wherein said phenyl and phenoxy independently are unsubstitutedor substituted with one halogen; or R¹ is R¹⁴R¹⁵NCO—, wherein R¹⁴ andR¹⁵ each are independently hydrogen, C₁₋₆-alkyl, aryl oraryl-C₁₋₆-alkyl, wherein each of said C₁₋₆-alkyl and aryl groupsindependently are unsubstituted or substituted with one substituentselected from the group consisting of halogen and C₁₋₆-alkoxy.
 18. Acompound according to claim 1, wherein R² is hydrogen.
 19. A compoundaccording to claim 1, wherein R³ is hydrogen.
 20. A compound accordingto claim 1, wherein R⁴ hydrogen or methoxy.
 21. A compound accordingclaim 1, wherein R⁵ hydrogen or methoxy.
 22. A compound according toclaim 1, wherein R⁶ hydrogen.
 23. A compound according to claim 1,wherein R^(7a) and R^(7b) are hydrogen.
 24. A compound according toclaim 1, wherein R^(8a) and R^(8b) are hydrogen.
 25. A compoundaccording to claim 1 selected from the group consisting of:1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid phenethyl-amide,1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenylmethanone,1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-fluoro-phenyl)methanone,1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3-phenyl-propan-1-one,1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid (3-chloro-propyl)amide,1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid (2-methoxy-phenyl)amide,1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester,3-Chloro-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2,2-dimethyl-propan-1-one,1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-[2-(4-Chloro-phenoxy)-pyridin-3-yl]-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester,1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-phenylmethanone,1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-p-tolylmethanone,1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-methoxy-phenyl)methanone,1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(2-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(2-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(4-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(4-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid phenethyl amide,1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-methoxy-phenyl)methanone,1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3-phenyl-propan-1-one,2-Ethyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one,1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-methoxy-phenyl)methanone,1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-phenylethanone,3-Cyclohexyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one,2-(4-Fluoro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)ethanone,1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid (3,4-dichloro-phenyl)amide,1-Cyclopropyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-pyridin-3-yl-methanone,1-[5-(4-Chloro-phenyl)-2-methyl-furan-3-yl]-1(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methano,2-(4-Chloro-phenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)ethanone1-(1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-propan-1-one,1-{2-[6-Fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid (2-ethyl-phenyl)amide,N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidin-1′-yl]]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cycloheptyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone,N-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl)acetamide,1-Cycloheptyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cycloheptyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone,1-(4-Fluorophenyl)-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cycloheptyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cycloheptyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-{1-[spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-Cyclopentyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone1-(4-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-(2-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cycloheptyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone,1-Cyclopentyl-1-(1-{2-[5-isopropylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,1-Cycloheptyl-1-{1-[2-(4-phenylpiperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-Cycloheptyl-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone,1-[1-(2-{2-[1-(4-Fluorophenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenylpiperidin-4-yl]-1-piperidin-1-yl-methanone,1-Cyclopentyl-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,8-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one1-Cycloheptyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]-1-(4-methyl-piperazin-1-yl)methanone,1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidine-4-carboxylicacid ethyl ester,1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-ethanone,1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)ethanone,1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-1-(4-fluoro-phenyl)methanone,1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-(4-methyl-piperazin-1-yl)methanone,1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cyclopentylmethanone,1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[piro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[4-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(2-Fluorophenyl)-1-(1-{2-[6-fluoro-3-methylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanoneN-[4-(3-Fluoro-phenyl)-1-(2-{2-[1-(4-fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-piperidin-4-yl]-acetamide,1-(2-Fluorophenyl)-1-{1-[spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-Cycloheptyl-1-(1-{2-[5-fluoro-1-methansulfonyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-(1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-1-piperidin-1-ylmethanone,1-{1-[2-(4-Benzyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-1-cycloheptylmethanone,1-(2-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-(1-{2-[(Chloro-trifluoromethyl-phenyl)-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone,1-(1-{2-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-cycloheptylmethanone,1-Cycloheptyl-1-(1-{2-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(7-Chloro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-cyclopentylmethanone,1-Cyclopentyl-1-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(2,3-Dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,N-[1-{2-[2-(1-Cycloheptyl-methanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide,1-(4-Fluoro-phenyl)-1-{1-[2-(4-phenyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-(1-{2-[4-(6-Chloro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,1-(4-Fluoro-phenyl)-1-(1-{2-[4-(3-fluoro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone1-Cycloheptyl-1-{1-[spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl}methanone,N-(1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide,1-(1-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(2-fluoro-phenyl)methanone,1-cycloheptyl-1-(1-{2-[spiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidine-4-carboxylicacid ethyl ester,1-(1-{2-[4-(4-Dimethylamino-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,1-Cyclopentyl-1-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-[1-(2-{2-[1-(4-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]ethanone,1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]ethanone,1-[1-(2-{2-[1-(2-Fluoro-phenyl)-methanoyl]-1,2,3,4-tetrahydro-isoquinolin-1-yl}-ethyl)-4-phenyl-piperidin-4-yl]-1-piperidin-1-yl-methanone,1-Cyclopentyl-1-{1-[2-(4-phenyl-piperidin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-(2-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-6,7-dimethoxy-1H-isoquinolin-2-yl)methanone,1-(4-Fluoro-phenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)methanone3,3-Dimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one,Cyclohexyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanoneCyclohexyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,Cyclohexyl-[1-{2-[spiro(benzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone,Cyclohexyl-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,N-{1-[2-(2-Cyclohexanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-phenyl-piperidin-4-yl}-acetamide,3,3-Dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one,Cyclohexyl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,Cyclohexyl-(1-{2-[4-(4-dimethylamino-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,3-Phenyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propanone,(1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl-methanone,2-Phenoxy-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-ethan-1-one,Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,Cyclohexyl-(1-{2-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,2-Propyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-pentan-1-one,2,2-Dimethyl-3-chlor-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one,Cyclohexyl-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,3,3-Dimethyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one,Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,2-Ethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one,2-Benzyloxy-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethan-1-one,Benzo[1,2,5]oxadiazol-5-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)]-ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone,(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl-methanone,1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one,3,5,5-Trimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-hexan-1-one3,5,5-Trimethyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one,2-Phenoxy-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethan-1-one,(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-(2,2-dichloro-cyclopropyl)-methanone,2-Benzyloxy-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-ethan-1-one,1-(1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one,1-(1-{2-[4-(2,3-Dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-butan-1-one,3,5,5-Trimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one,2,2-Dimethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one,3-Cyclohexyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one,Furan-2-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone,N-(4-Phenyl-1-{2-[2-(3,5,5-trimethyl-hexanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-acetamide,Quinoxalin-2-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-methanone,3-Cyclohexyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-propan-1-one,Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,(Tetrahydro-pyran-4-yl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,2-Propyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-pentan-1-one,2-Ethyl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one,3-Phenyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one,3,3-Dimethyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-butan-1-one,(1-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-ethyl}-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-(2,2-dichloro-cyclopropyl)-methanone,1,2,3,4-tetrahydro-naphthalene-2-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,(4-Methylsulfanyl-phenyl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,3,5,5-Trimethyl-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-hexan-1-one,3-Phenyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one,Furan-2-yl-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,2-Benzyloxy-1-(1-{2-[4-(2-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone,1-(1-{2-[4-(4-Chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-2-phenoxy-ethanone,Quinoxalin-2-yl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,2,2-Dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one,(2,2-Dichloro-cyclopropyl)-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,4-Methylsulfanyl-phenyl-(1-{2-[spiro(5-methyl-isobenzofuran-3H-1,4′-piperidine-1′-yl)]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,(2,2-Dichloro-cyclopropyl)-(1-{2-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,1-(1-{2-[4-(4-Isopropyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-3,5,5-trimethyl-hexan-1-one,2,2-Dichloro-cyclopropyl-(1-{2-[spiro(isobenzofuran-3H-1,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,N-(4-Phenyl-1-{2-[2-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)-acetamide,Benzo[1,2,5]oxadiazol-5-yl-(1-{2-[4-(4-chloro-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,N-(1-{2-[2-(3,3-Dimethyl-butyryl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)-acetamide,3-Chloro-2,2-dimethyl-1-(1-{2-[4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinolin-2-yl)-propan-1-one,Tetrahydro-pyran-4-yl-[1-{2-[spiro(5-fluor-benzofuran-2H-3,4′-piperidine-1′-yl)-]ethyl}-3,4-dihydro-1H-isoquinoline-2-yl]-butan-1-one,1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-Chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone,1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5chloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone,1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone,1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro1H-indol-3,4′-piperidin-1′-yl]-ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone,1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl}methanone,1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone,1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-methanone,1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl)-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)-methanone,1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-3,4-dihydro-5-fluoro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-(4-Fluorophenyl)-1-{1-[-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone,1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-dichloro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(5-Fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluoro-phenyl)methanone,1-Cyclopentyl-1-(1-{2-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[6-fluorospiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[6-trifluoromethylspiro[isobenzofuran-1(3H),4′-piperidine-1′-yl]ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluorophenyl)-piperidin-4-yl]acetamide,N-[1-{2-[2-(1-Cyclopentyl-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,N-[1-{2-[2-(1-(4-Fluorophenyl)-methanoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenylpiperidin-4-yl]acetamide,1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-Cyclopentyl-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro1H-indol-3,4′-piperidin-1′-yl]-ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-(4-Fluorophenyl)-1-{1-[1-acetyl-spiro[2,3-dihydro-5-fluoro-1H-indol-3,4′-piperidin-1′-yl]ethyl]-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl}methanone,1-Cyclopentyl-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[4-(3-trifluoromethylphenyl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorophenyl)methanone,1-(1-{2-[4-(6-Fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-1-(cyclopentyl)methanone,1-(4-Fluorophenyl)-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1-isoquinolin-2-yl)-methanone,1-(4-Fluorophenyl)-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone,1-Cyclopentyl-1-(1-{2-[5,6-difluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,and1-Cyclopentyl-1-({2-[6-fluorospiro[benzofuran-1(3H),4′-piperidine-1′-yl]-ethyl}-5,6-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)methanone.26. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 and one or morepharmaceutically acceptable carrier or diluent.
 27. A pharmaceuticalpreparation for the treatment of a disease of the central nervous systemcomprising a therapeutically effective amount of a compound according toclaim 1 and one or more carrier or diluent suitable for administrationto a patient in need of said treatment.
 28. A method of treatment of adisease of the central nervous system comprising, administering to apatient in need of said treatment a therapeutically effective amount ofa compound according to claim
 1. 29. The method according to claim 28,wherein said disease of the central nervous system is selected from thegroup consisting of depression, manic depression, bipolar disorder,dysthymia, mixed anxiety depression, generalised anxiety disorder,social anxiety disorder, panic anxiety disorder, post traumatic stressdisorder, obsessive compulsive disorder, acute stress disorder, phobia,pre-menstrual dysphoric disorder, psychosis, Huntington's disease,Parkinson's dementia, adjustment disorders, pain, emesis, migraine,epilepsia, obesity and cerebrovascular disease.
 30. The method accordingto claim 29, wherein said disease of the central nervous system isselected from the group consisting of depression, manic depression,bipolar disorder, dysthymia, mixed anxiety depression, generalizedanxiety disorder, social anxiety disorder, panic anxiety disorder,post-traumatic stress disorder, obsessive compulsive disorder, acutestress disorder, phobia, pre-menstrual dysphoric disorder and psychosis.31. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 25 and one or morepharmaceutically acceptable carrier or diluent.
 32. A pharmaceuticalpreparation for the treatment of a disease of the central nervous systemcomprising a therapeutically effective amount of a compound according toclaim 25 and one or more carrier or diluent suitable for administrationto a patient in need of said treatment.
 33. A method of treatment of adisease of the central nervous system comprising, administering to apatient in need of said treatment a therapeutically effective amount ofa compound according to claim
 25. 34. The method according to claim 33,wherein said disease of the central nervous system is selected from thegroup consisting of depression, manic depression, bipolar disorder,dysthymia, mixed anxiety depression, generalised anxiety disorder,social anxiety disorder, panic anxiety disorder, post traumatic stressdisorder, obsessive compulsive disorder, acute stress disorder, phobia,pre-menstrual dysphoric disorder, psychosis, Huntington's disease,Parkinson's dementia, adjustment disorders, pain, emesis, migraine,epilepsia, obesity and cerebrovascular disease.
 35. The method accordingto claim 34, wherein said disease of the central nervous system isselected from the group consisting of depression, manic depression,bipolar disorder, dysthymia, mixed anxiety depression, generalizedanxiety disorder, social anxiety disorder, panic anxiety disorder,post-traumatic stress disorder, obsessive compulsive disorder, acutestress disorder, phobia, pre-menstrual dysphoric disorder and psychosis.36. A compound selected from the group consisting of:N-(4-(3-Fluoro-phenyl)-1-{2-[2-(2-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide,N-(4-(3-Fluoro-phenyl)-1-{2-[2-(2-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide,N-[1-{2-[2-(4-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide,N-[1-{2-[2-(4-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide,N-[1-{2-[2-(4-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide,N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-isopropyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide,N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-methyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide,N-[1-{2-[2-(3-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide,N-[1-{2-[2-(2-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide,N-(1-{2-[2-(4-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide,N-(1-{2-[2-(2,4-Dichloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide,N-[1-{2-[2-(2,4-Dichloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide,N-[1-{2-[2-(Benzo[1,2,5]oxadiazole-5-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide,N-(4-(3-Fluoro-phenyl)-1-{2-[2-(naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide,N-[1-[2-(2-Cyclopentanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide,N-(1-{2-[2-(4-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide,N-[1-{2-[2-(Benzo[b]thiophene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide,N-[1-{2-[2-(6-Fluoro-4H-benzo[1,3]dioxine-8-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide,N-[1-{2-[2-(3-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide,N-[1-{2-[2-(2-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]acetamide,N-(1-{2-[2-(4-Methyl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide,N-[1-{2-[2-(2-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-(3-fluoro-phenyl)-piperidin-4-yl]-acetamide,N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide,N-(1-{2-[2-(3-Chloro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl}-4-phenyl-piperidin-4-yl)acetamide,N-(1-{2-[2-(4-Fluoro-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide,N-{1-[2-(2-Cycloheptanecarbonyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-ethyl]-4-phenyl-piperidin-4-yl}-acetamide,N-(1-{2-[2-(3-Bromo-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide,N-(4-(3-Fluoro-phenyl)-1-{2-[2-(3-methoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide,N-(4-(3-Fluoro-phenyl)-1-{2-[2-(thiophene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide,N-(4-(3-Fluoro-phenyl)-1-{2-[2-(4-pyrazol-1-yl-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-piperidin-4-yl)acetamide,N-(1-{2-[2-(Naphthalene-1-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-ethyl}-4-phenyl-piperidin-4-yl)acetamide;wherein the compound is prepared by acylating an enantiomeric amine offormula V:

wherein: R² is hydrogen, trifluoromethyl or C₁₋₆-alkyl; R³-R⁶, R^(7a),R^(7b), R^(8a) and R^(8b) each are independently hydrogen, halogen,cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl, aminocarbonyl,C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl orC₁₋₆-alkylsulfonyl; R⁹ is benzyl, benzoyl, 2,3-dihydrobenzofuranyl,mono- or bicyclic aryl, or heteroaryl wherein each benzyl, benzoyl, arylor heteroaryl optionally is substituted with one or more substituentsselected from halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino,C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl,aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl,fluoromethyl and trifluoromethylsulfonyl; Q is C, N or CR¹⁰; wherein R¹⁰is hydrogen, halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, amino,C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonyl,aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl,fluoromethyl, trifluoromethylsulfonyl, —NR³⁰COR³¹ wherein R³⁰ ishydrogen or C₁₋₆-alkyl and R³¹ is C₁₋₆-alkyl, —COOR¹⁶ wherein R¹⁶ ishydrogen or C₁₋₆-alkyl, or —CONR¹⁷R¹⁸ wherein R¹⁷ and R¹⁸ each areindependently are selected from hydrogen or C₁₋₆-alkyl or R¹⁷ and R¹⁸,taken together with the nitrogen to which they are attached, form apiperidinyl, piperazinyl or morpholinyl group, wherein said piperidinyl,piperazinyl and morpholinyl group is unsubstituted or substituted with aC₁₋₆-alkyl; or when Q is CR¹⁰, R⁹ and R¹⁰, taken together with a carbonto which they are attached, form a cyclic structure selected from thegroup consisting of:

wherein Q′ is a carbon shared with a piperidine ring, whereby saidcyclic structure together with said piperidine ring forms a spirostructure; and X, Y, and Z each are independently O, NR¹⁹, CR²³R²⁴,S(O)_(n) or a bond, wherein: R¹⁹ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆-alkyl,trifluoromethyl, acyl, thioacyl or trifluoromethylsulfonyl; R¹⁹ isR²⁰SO₂—, R²⁰OCO— or R²⁰SCO— wherein R²⁰ is C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl or aryl; orR¹⁹ is R²¹R²²NCO— or R²¹R²²NCS—, wherein R²¹ and R²² each areindependently hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, or aryl, wherein said arylis unsubstituted or substituted with one or more substituents selectedfrom C₁₋₆-alkyl or halogen; or R²¹ and R²², taken together with theN-atom to which they are linked, form a pyrrolidinyl, piperidinyl orperhydroazepinyl group; and R²³ and R²⁴ each are independently hydrogen,halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl or heteroaryl, whereinsaid aryl is unsubstituted or substituted with one or more substituentsselected from C₁₋₆-alkyl, halogen, amino, C₁₋₆-alkylamino, or NR²⁵R²⁶,wherein R²⁵ and R²⁶ each are independently C₁₋₆-alkyl,C₁₋₆-alkylcarbonyl, aminocarbonyl, C₁₋₆-alkylaminocarbonyl,di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy,trifluoromethyl, trifluoromethylsulfonyl or C₁₋₆-alkylsulfonyl; or R²⁵and R²⁶, taken together, with the N-atom to which they are linked, forma pyrrolidinyl, piperidinyl, perhydroazepinyl or morpholinyl group; orR²³ and R²⁴, taken together form an oxo group; and n is 0, 1 or 2;provided that no more than one of X, Y and Z may be a bond, and providedthat two adjacent X, Y or Z may not at the same time be O and S; and A¹,A², A³ and A⁴ each are independently N or CR²⁷, wherein R²⁷ is hydrogen,halogen, cyano, nitro, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkylcarbonyl,aminocarbonyl, C₁₋₆-alkylaminocarbonyl, di-(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, hydroxy, trifluoromethyl, difluoromethyl,fluoromethyl, trifluoromethylsulfonyl, C₁₋₆-alkylsulfonyl, amino, orNR²⁸R²⁹, wherein R²⁸ and R²⁹ each are independently hydrogen orC₁₋₆-alkyl; or R²⁸ and R²⁹, taken together with the N-atom to which theyare linked, form a pyrrolidinyl, piperidinyl, perhydroazepinyl ormorpholinyl group; provided that only one of A¹, A², A³ and A⁴ may be N;and provided that a dotted line emanating from Q is a bond when Q is C,and no bond when Q is CR¹⁰ or N; and wherein the enantiomeric amine offormula V is the slower eluting enantiomer of a pair of enantiomericamines of formula V when the pair is separated by supercritical HPLC at20 Mpa on a system comprising at least one chiralcel OD column and aneluent comprising carbondioxide (75%), 2-propanol (24.75%), diethylamine(0.125%) and trifluoracetic acid (0.125%).